Nitrogen-containing bicyclic heterocycles for use as antibacterials

ABSTRACT

Cyclohexane and cyclohexene derivatives and pharmaceutically acceptable derivatives thereof useful in methods of treatment of bacterial infections in mammals, particularly man.

This invention relates to novel compounds, compositions containing themand their use as antibacterials.

WO099/37635, WO00/21948, WO00/21952, WO00/43383, WO00/78748, WO01/07433,WO01/07432, WO02/08224, WO02/24684 and WO01/25227 disclose quinoline andnaphthyridine derivatives having antibacterial activity.

This invention provides a compound of formula (I) or a pharmaceuticallyacceptable derivative thereof:

wherein:

-   one of Z¹, Z², Z³, Z⁴ and Z⁵ is N, one is CR^(1a) and the remainder    are CH, or one of Z¹, Z², Z³, Z⁴ and Z⁵ is CR^(1a) and the remainder    are CH;-   R^(v) and R^(w) are hydrogen or R^(v) and R^(w) together are a bond;-   R¹ and R^(1a) are independently selected from hydrogen; hydroxy;    (C₁₋₆) alkoxy optionally substituted by (C₁₋₆)alkoxy, amino,    piperidyl, guanidino or amidino any of which is optionally    N-substituted by one or two (C₁₋₆)alkyl, acyl or    (C₁₋₆)alkylsulphonyl groups, CONH2, hydroxy, (C₁₋₆)alkylthio,    heterocyclylthio, heterocyclyloxy, arylthio, aryloxy, acylthio,    acyloxy or (C₁₋₆)alkylsulphonyloxy, (C₁₋₆)alkoxy-substituted    (C₁₋₆)alkyl; halogen; (C₁₋₆)alkyl; (C₁₋₆)alkylthio; trifluromethyl;    nitro; azido; acyl; acyloxy; acylthio; (C₁₋₆)alkylsulphonyl;    (C₁₋₆)alkylsulphoxide; arylsulphonyl; arylsulphoxide or an amino,    piperidyl, guanidino or amidino group optionally N-substituted by    one or two (C₁₋₆)alkyl, acyl or (C₁₋₆)alkylsulphonyl groups, or when    Z¹ is CR^(1a), R¹ and R^(1a) may together represent    (C₁₋₂)akylenedioxy,-   provided that when Z¹, Z², Z³, Z⁴ and Z⁵ are CR^(1a) or CH, then R¹    is not hydrogen;-   R² is hydrogen or (C₁₋₄)alkyl or (C₂₋₄)alkenyl optionally    substituted with 1 to 3 groups selected from:-   amino optionally substituted by one or two (C₁₋₄)alkyl groups;    carboxy; (C₁₋₄)alkoxycarbonyl; (C₁₋₄)alkylcarbonyl;    (C₂₋₄)alkenyloxycarbonyl; (C₂₋₄)alkenylcarbonyl; aminocarbonyl    wherein the amino group is optionally substituted by hydroxy,    (C₁₋₄)alkyl, hydroxy(C₁₋₄)alkyl, aminocarbonyl(C₁₋₄)alkyl,    (C₂₋₄)alkenyl, (C₁₋₄)alkylsulphonyl, trifluoromethylsulphonyl,    (C₂₋₄)alkenylsulphonyl, (C₁₋₄)alkoxycarbonyl, (C₁₋₄)alkylcarbonyl,    (C₂₋₄)alkenyloxycarbonyl or (C₂₋₄)alkenylcarbonyl; cyano;    tetrazolyl; 2-oxo-oxazolidinyl optionally substituted by R¹⁰;    3-hydroxy-3-cyclobutene-1,2-dione-4-yl; 2,4-thiazolidinedione-5-yl;    tetrazol-5-ylaminocarbonyl; 1,2,4-triazol-5-yl optionally    substituted by R¹⁰; 5-oxo-1,2,4-oxadiazol-3-yl; halogen;    (C₁₋₄)alkylthio; trifluoromethyl; hydroxy optionally substituted by    (C₁₋₄)alkyl, (C₂₋₄)alkenyl, (C₁₋₄)alkoxycarbonyl,    (C₁₋₄)alkylcarbonyl, (C₂₋₄)alkenyloxycarbonyl,    (C₂₋₄)alkenylcarbonyl; oxo; (C₁₋₄)alkylsulphonyl;    (C₂₋₄)alkenylsulphonyl; or (C₁₋₄)aminosulphonyl wherein the amino    group is optionally substituted by (C₁₋₄)alkyl or (C₂₋₄)alkenyl;-   R³ is hydrogen; or-   when R^(v) and R^(w) are a bond, R³ is in the 2-, 3- or 4-position    and when R^(v) and R^(w) are not a bond, R³ is in the 1-, 2-, 3- or    4-position and R³ is:-   carboxy; (C₁₋₆)alkoxycarbonyl; aminocarbonyl wherein the amino group    is optionally substituted by hydroxy, (C₁₋₆)alkyl,    hydroxy(C₁₋₆)alkyl, aminocarbonyl(C₁₋₆)alkyl, (C₂₋₆)alkenyl,    (C₁₋₆)alkylsulphonyl, trifluoromethylsulphonyl,    (C₂₋₆)alkenylsulphonyl, (C₁₋₆)alkoxycarbonyl, (C₁₋₆)alkylcarbonyl,    (C₂₋₆)alkenyloxycarbonyl or (C₂₋₆)alkenylcarbonyl and optionally    further substituted by (C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl,    aminocarbonyl(C₁₋₆)alkyl or (C₂₋₆)alkenyl; cyano; tetrazolyl;    2-oxo-oxazolidinyl optionally substituted by R¹⁰;    3-hydroxy-3-cyclobutene-1,2-dione-4-yl; 2,4-thiazolidinedione-5-yl;    tetrazol-5-ylaminocarbonyl; 1,2,4-triazol-5-yl optionally    substituted by R¹⁰; or 5-oxo-1,2,4-oxadiazol-3-yl; or-   (C₁₋₄)alkyl or ethenyl optionally substituted with any of the groups    listed above for R³ and/or 0 to 2 groups R¹² independently selected    from:    -   halogen; (C₁₋₆)alkylthio; trifluoromethyl; (C₁₋₆)alkoxycarbonyl;        (C₁₋₆)alkylcarbonyl; (C₂₋₆)alkenyloxycarbonyl;        (C₂₋₆)alkenylcarbonyl; hydroxy optionally substituted by        (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₁₋₆)alkoxycarbonyl,        (C₁₋₆)alkylcarbonyl, (C₂₋₆)alkenyloxycarbonyl,        (C₂₋₆)alkenylcarbonyl or aminocarbonyl wherein the amino group        is optionally substituted by (C₁₋₆)alkyl, (C₂₋₆)alkenyl,        (C₁₋₆)alkylcarbonyl or (C₂₋₆)alkenylcarbonyl; amino optionally        mono- or disubstituted by (C₁₋₆)alkoxycarbonyl,        (C₁₋₆)alkylcarbonyl, (C₂₋₆)alkenyloxycarbonyl,        (C₂₋₆)alkenylcarbonyl, (C₁₋₆)alkyl, (C₂₋₆)alkenyl,        (C₁₋₆)alkylsulphonyl, (C₂₋₆)alkenylsulphonyl or aminocarbonyl        wherein the amino group is optionally substituted by (C₁₋₆)alkyl        or (C₂₋₆)alkenyl; aminocarbonyl wherein the amino group is        optionally substituted by (C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl,        aminocarbonyl(C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₁₋₆)alkoxycarbonyl,        (C₁₋₆)alkylcarbonyl, (C₂₋₆)alkenyloxycarbonyl or        (C₂₋₆)alkenylcarbonyl and optionally further substituted by        (C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl, aminocarbonyl(C₁₋₆)alkyl or        (C₂₋₆)alkenyl; oxo; (C₁-6)alkylsulphonyl;        (C₂₋₆)alkenylsulphonyl; or (C₁₋₆)aminosulphonyl wherein the        amino group is optionally substituted by (C₁₋₆)acyl or        (C₂₋₆)alkenyl; or-   hydroxy optionally substituted by (C₁₋₆)alkyl, (C₂₋₆)alkenyl,    (C₁₋₆)alkoxycarbonyl, (C₁₋₆)alkylcarbonyl, (C₂₋₆)alkenyloxycarbonyl,    (C₂₋₆)alkenylcarbonyl or aminocarbonyl wherein the amino group is    optionally substituted by (C₁₋₆)alkyl, (C₂₋₆)alkenyl,    (C₁₋₆)alkylcarbonyl or (C₂₋₆)alkenylcarbonyl; or-   amino optionally mono- or disubstituted by (C₁₋₆)alkoxycarbonyl;    (C₁₋₆)alkylcarbonyl, (C₂₋₆)alkenyloxycarbonyl,    (C₂₋₆)alkenylcarbonyl, (C₁₋₆)alkyl, (C₂₋₆)alkenyl,    (C₁₋₆)alkylsulphonyl, (C₂₋₆)alkenylsulphonyl or aminocarbonyl    wherein the amino group is optionally substituted by (C₁₋₆)alkyl or    (C₂₋₆)alkenyl;-   provided that when R³ is in the 4-position it is not optionally    substituted hydroxyl or amino;-   in addition when R³ is disubstituted with a hydroxy or amino    containing substituent and a carboxy containing substituent these    may optionally together form a cyclic ester or amide linkage,    respectively;-   R¹⁰ is selected from (C₁₋₄)alkyl and (C₂₋₄)alkenyl either of which    may be optionally substituted by a group R¹² as defined above;    carboxy; aminocarbonyl wherein the amino group is optionally    substituted by hydroxy, (C₁₋₆)alkyl, (C₂₋₆)alkenyl,    (C₁₋₆)alkylsulphonyl, trifluoromethylsulphonyl,    (C₂₋₆)alkenylsulphonyl, (C₁-6)alkoxycarbonyl, (C₁₋₆)alkylcarbonyl,    (C₂₋₆)alkenyloxycarbonyl or (C₂₋₆)alkenylcarbonyl and optionally    further substituted by (C₁₋₆)alkyl or (C₂₋₆)alkenyl;    (C₁₋₆)alkylsulphonyl; trifluoromethylsulphonyl;    (C₂₋₆)alkenylsulphonyl; (C₁₋₆)alkoxycarbonyl; (C₁₋₆)alkylcarbonyl;    (C₂₋₆)alkenyloxycarbonyl; and (C₂₋₆)alkenylcarbonyl;-   R⁴ is a group —CH₂—R⁵ ₁, in which R⁵ ₁ is selected from:    -   (C₄₋₈)alkyl; hydroxy(C₄₋₈)alkyl; (C₁₋₄)alkoxy(C₄₋₈)alkyl;        (C₁₋₄)alkanoyloxy(C₄₋₈)alkyl; (C₃₋₈)cycloalkyl(C₄₋₈)alkyl;        hydroxy-, (C₁₋₆)alkoxy- or        (C₁₋₆)alkanoyloxy-(C₃₋₈)cycloalkyl(C₄₋₈)alkyl; cyano(C₄₋₈)alkyl;        (C₄₋₈)alkenyl; (C; 8)alkynyl; tetrahydrofuryl; mono- or        di-(C₁₋₆)alkylamino(C₄₋₈)alkyl; acylamino(C₄₋₈)alkyl;        (C₁₋₆)alkyl- or acyl-aminocarbonyl(C₄₋₈)alkyl; mono- or        di-(C₁₋₆)alkylamino(hydroxy) (C₄₋₈)alkyl; or-   R⁴ is a group —U—R⁵ ₂ where R⁵ ₂ is an optionally substituted    bicyclic carbocyclic or heterocyclic ring system (A):    containing up to four heteroatoms in each ring in which    -   at least one of rings (a) and (b) is aromatic;    -   X¹ is C or N when part of an aromatic ring or CR¹⁴ when part of        a non aromatic ring;    -   X² is N, NR¹³, O, S(O)_(x), CO or CR¹⁴ when part of an aromatic        or non-aromatic ring or may in addition be CR¹⁴R¹⁵ when part of        a non aromatic ring;    -   X³ and X⁵ are independently N or C;    -   Y¹ is a 0 to 4 atom linker group each atom of which is        independently selected from N, NR¹³, O, S(O)_(X), CO and CR¹⁴        when part of an aromatic or non-aromatic ring or may        additionally be CR¹⁴R¹⁵ when part of a non aromatic ring,    -   Y² is a 2 to 6 atom linker group, each atom of Y² being        independently selected from N, NR¹³, O, S(O)_(x), CO and CR¹⁴        when part of an aromatic or non-aromatic-ring or may        additionally be CR¹⁴R¹⁵ when part of a non aromatic ring; each        of R¹⁴ and R¹⁵ is independently selected from: H;        (C₁₋₄)alkylthio; halo; carboxy(C₁₋₄)alkyl; halo(C₁₋₄)alkoxy;        halo(C₁₋₄)alkyl; (C₁₋₄)alkyl; (C₂₋₄)alkenyl;        (C₁₋₄)alkoxycarbonyl; formyl; (C₁₋₄)alkylcarbonyl;        (C₂₋₄)alkenyloxycarbonyl; (C₂₋₄)alkenylcarbonyl;        (C₁₋₄)alkylcarbonyloxy; (C₁₋₄)alkoxycarbonyl(C₁₋₄)alkyl;        hydroxy; hydroxy(C₁₋₄)alkyl; mercapto(C₁₋₄)alkyl; (C₁₋₄)alkoxy;        nitro; cyano; carboxy; amino or aminocarbonyl optionally        substituted as for corresponding substituents in R³;        (C₁₋₄)alkylsulphonyl; (C₂₋₄)alkenylsulphonyl; or aminosulphonyl        wherein the amino group is optionally substituted by (C₁₋₄)alkyl        or (C₂₋₄)alkenyl; aryl; aryl(C₁₋₄)alkyl; aryl(C₁₋₄)alkoxy;    -   each R¹³ is independently H; trifluoromethyl; (C₁₋₄)alkyl        optionally substituted by hydroxy, carboxy,        (C₁₋₆)alkoxycarbonyl, (C₁₋₆)alkoxy, (C₁₋₆)alkylthio, halo or        trifluoromethyl; (C₂₋₄)alkenyl; aryl; aryl (C₁₋₄)alkyl;        arylcarbonyl; heteroarylcarbonyl; (C₁₋₄)alkoxycarbonyl;        (C₁₋₄)alkylcarbonyl; formyl; (C₁₋₆)alkylsulphonyl; or        aminocarbonyl wherein the amino group is optionally substituted        by (C₁₋₄)alkoxycarbonyl, (C₁₋₄)alkylcarbonyl,        (C₂₋₄)alkenyloxycarbonyl, (C₂₋₄)alkenylcarbonyl, (C₁₋₄)alkyl or        (C₂₋₄)alkenyl and optionally further substituted by (C₁₋₄)alkyl        or (C₂₋₄)alkenyl;    -   each x is independently 0, 1 or 2;-   U is CO, SO₂ or CH₂; or-   R⁴ is a group —X^(1a)—X^(2a)—X^(3a)—X^(4a) in which:    -   X^(1a) is CH₂, CO or SO₂;    -   X^(2a) is CR^(14a)R^(15a);    -   X^(3a) is NR^(13a), O, S, SO₂ or CR^(14a)R^(15a); wherein:    -   each of R^(14a) and R^(15a) is independently selected from the        groups listed above for R¹⁴ and R¹⁵, provided that R^(14a) and        R^(15a) on the same carbon atom are not both selected from        optionally substituted hydroxy and optionally substituted amino;        or R^(14a) and R^(15a) together represent oxo;    -   R^(13a) is hydrogen; trifluoromethyl; (C₁₋₆)alkyl;        (C₂₋₆)alkenyl; (C₁₋₆)alkoxycarbonyl; (C₁₋₆)alkylcarbonyl; or        aminocarbonyl wherein the amino group is optionally substituted        by (C₁₋₆)alkoxycarbonyl, (C₁₋₆)alkylcarbonyl,        (C₂₋₆)alkenyloxycarbonyl, (C₂₋₆)alkenylcarbonyl, (C₁₋₆)alkyl or        (C₂₋₆)alkenyl and optionally further substituted by (C₁₋₆)alkyl        or (C₂₋₆)alkenyl; or    -   two R^(14a) groups or an R^(13a) and an R^(14a) group on        adjacent atoms together represent a bond and the remaining        R^(13a), R^(14a) and R^(15a) groups are as above defined; or    -   two R^(14a) groups and two R^(15a) groups on adjacent atoms        together represent bonds such that X^(2a) and X^(3a) is triple        bonded;    -   X^(4a) is phenyl or C or N linked monocyclic aromatic 5- or        6-membered heterocycle containing up to four heteroatoms        selected from O, S and N and: optionally C-substituted by up to        three groups selected from (C₁₋₄)alkylthio; halo;        carboxy(C₁₋₄)alkyl; halo(C₁₋₄)alkoxy; halo(C₁₋₄)alkyl;        (C₁₋₄)alkyl; (C₂₋₄)alkenyl; (C₁₋₄)alkoxycarbonyl; formyl;        (C₁₋₄)alkylcarbonyl; (C₂₋₄)alkenyloxycarbonyl;        (C₂₋₄)alkenylcarbonyl; (C₁₋₄)alkylcarbonyloxy;        (C₁₋₄)alkoxycarbonyl(C₁₋₄)alkyl; hydroxy; hydroxy(C₁₋₄)alkyl;        mercapto(C₁₋₄)alkyl; (C₁₋₄)alkoxy; nitro; cyano; carboxy; amino        or aminocarbonyl optionally substituted as for corresponding        substituents in R³; (C₁₋₄)alkylsulphonyl;        (C₂₋₄)alkenylsulphonyl; or aminosulphonyl wherein the amino        group is optionally substituted by (C₁₋₄)alkyl or (C₂₋₄)alkenyl;        aryl, aryl(C₁₋₄)alkyl or aryl(C₁₋₄)alkoxy; and-   optionally N substituted by trifluoromethyl; (C₁₋₄)alkyl optionally    substituted by hydroxy, (C₁₋₆)alkoxy, (C₁₋₆)alkylthio, halo or    trifluoromethyl; (C₂₋₄)alkenyl; aryl; aryl(C₁₋₄)alkyl;    (C₁₋₄)alkoxycarbonyl; (C₁₋₄)alkylcarbonyl; formyl;    (C₁₋₆)alkylsulphonyl; or aminocarbonyl wherein the amino group is    optionally substituted by (C₁₋₄)alkoxycarbonyl, (C₁₋₄)alkylcarbonyl,    (C₂₋₄)alkenyloxycarbonyl, (C₂₋₄)alkenylcarbonyl, (C₁₋₄)alkyl or    (C₂₋₄)alkenyl and optionally further substituted by (C₁₋₄)alkyl or    (C₂₋₄)alkenyl;-   n is 0 or 1 and AB is NR¹¹ CO, CONR¹¹, CO—CR⁸R⁹, CR⁶R⁷—CO, O—CR⁸R⁹,    CR⁶R⁷—O, NHR¹¹—CR⁸R⁹, CR⁶R⁷—NHR¹¹, NR¹¹SO₂, CR⁶R⁷—SO₂ or    CR⁶R⁷—CR⁸R⁹, provided that when R^(v) and R^(w) are a bond and n=0,    B is not NR¹¹, O or SO₂, or n is 0 and AB is NH—CO—NH or NH—CO—O and    R^(v)/R^(w) are not a bond;-   or n is 0 and AB is CR⁶R⁷SO₂NR², CR⁶R⁷CONR² or CR⁶R⁷CH₂NR² and    R^(v)/R^(w) are not a bond;-   provided that R⁶ and R⁷, and R⁸ and R⁹ are not both optionally    substituted hydroxy or amino; and wherein:-   each of R⁶, R⁷, R⁸ and R⁹ is independently selected from: H;    (C₁₋₆)alkoxy, (C₁₋₆)alkylthio; halo; trifluoromethyl; azido;    (C₁₋₆)alkyl; (C₂₋₆)alkenyl; (C₁₋₆)alkoxycarbonyl;    (C₁₋₆)alkylcarbonyl; (C₂₋₆)alkenyloxycarbonyl;    (C₂₋₆)alkenylcarbonyl; hydroxy, amino or aminocarbonyl optionally    substituted as for corresponding substituents in R³;    (C₁₋₆)alkylsulphonyl; (C₂₋₆)alkenylsulphonyl; or    (C₁₋₆)aminosulphonyl wherein the amino group is optionally    substituted by (C₁₋₆)alkyl or (C₂₋₆)alkenyl;-   or R⁶ and R⁸ together represent a bond and R⁷ and R⁹ are as above    defined;-   and each R¹¹ is independently H; trifluoromethyl; (C₁₋₆)alkyl;    (C₂₋₆)alkenyl; (C₁₋₆)alkoxycarbonyl; (C₁₋₆)alkylcarbonyl; or    aminocarbonyl wherein the amino group is optionally substituted by    (C₁₋₆)alkoxycarbonyl, (C₁₋₆)alkylcarbonyl, (C₂₋₆)alkenyloxycarbonyl,    (C₂₋₆)alkenylcarbonyl, (C₁₋₆)alkyl or (C₂₋₆)alkenyl and optionally    further substituted by (C₁₋₆)alkyl or (C₂₋₆)alkenyl;-   or where one of R³ and R⁶, R⁷, R⁸ or R⁹ contains a carboxy group and    the other contains a hydroxy or amino group they may together form a    cyclic ester or amide linkage or where —R³ contains a carboxy group    and A or B is NH they may be condensed to form a cyclic amide.

The invention also provides the use of a compound of formula (I) or apharmaceutically acceptable derivative thereof in the manufacture of amedicament for use in the treatment of bacterial infections in mammals.

The invention also provides a pharmaceutical composition, in particularfor use in the treatment of bacterial infections in mammals, comprisinga compound of formula (I), or a pharmaceutically acceptable derivativethereof, and a pharmaceutically acceptable carrier.

The invention further provides a method of treatment of bacterialinfections in mammals, particularly in man, which method comprises theadministration to a mammal in need of such treatment of an effectiveamount of a a compound of formula (I), or a pharmaceutically acceptablederivative thereof.

In one aspect R¹ and R^(1a) do not together represent(C₁₋₂)alkylenedioxy, and R13 does not represent carboxy or(C₁₋₆)alkoxycarbonyl.

Preferably Z⁵ is CH or N, Z³ is CH or CF and Z¹, Z² and Z⁴ are each CH,or Z¹ is N, Z³ is CH or CF and Z², Z⁴ and Z⁵ are each CH.

When R¹ or R^(1a) is substituted alkoxy it is preferably (C₂₋₆)alkoxysubstitituted by optionally N-substituted amino, guanidino or amidino,or (C₁₋₆)alkoxy substituted by piperidyl. Suitable examples of R¹ alkoxyinclude methoxy, trifluoromethoxy, n-propyloxy, i-butyloxy,aminoethyloxy, aminopropyloxy, aminobutyloxy, aminopentyloxy,guanidinopropyloxy, piperidin-4-ylmethyloxy, phthalimido pentyloxy or2-aminocarbonylprop-2-oxy. Preferably R¹ is methoxy,amino(C₃₋₅)alkyloxy, guanidino(C₃₋₅)alkyloxy, piperidyl(C₃₋₅)alkyloxy,nitro or fluoro.

Preferably R¹ and R^(1a) are independently methoxy, amino(C₃₋₅)alkyloxy,guanidino(C₃₋₅)alkyloxy, piperidyl(C₃₋₅)alkyloxy, nitro or fluoro; morepreferably methoxy, fluoro, amino(C₃₋₅)allyloxy orguanidino(C₃₋₅)alkyloxy. Preferably R^(1a) is H or F. Most preferably R¹is methoxy or fluoro and R^(1a) is H or when Z³ is CR^(1a) it may beC—F.

When Z⁵ is CR^(1a), R^(1a) is preferably hydrogen, cyano, hydroxymethylor carboxy, most preferably hydrogen.

R² is preferably hydrogen; (C₁₋₄)alkyl substituted with carboxy,optionally substituted hydroxy, optionally substituted aminocarbonyl,optionally substituted amino or (C₁₋₄)alkoxycarbonyl; or (C₂₋₄)alkenylsubstituted with (C₁₋₄)alkoxycarbonyl or carboxy. More preferred groupsfor R² are hydrogen, carboxymethyl, hydroxyethyl, aminocarbonylmethyl,ethoxycarbonylmethyl, ethoxycarbonylallyl and carboxyallyl, mostpreferably hydrogen.

Preferred examples of R³ include hydrogen; hydroxy; (C₁₋₄) alkyl;ethenyl; optionally substituted 1-hydroxy-(C₁₋₄) alkyl; optionallysubstituted aminocarbonyl; carboxy(C₁₋₄)alkyl; optionally substitutedaminocarbonyl(C₁₋₄)allyl; cyano(C₁₋₄)alkyl; optionally substituted2-oxo-oxazolidinyl and optionally substituted2-oxo-oxazolidinyl(C₁₋₄₋alkyl). More preferred R³ groups are hydrogen;hydroxy; CONH₂; 1-hydroxyalkyl e.g. CH₂OH, CH(OH)CH₂CN; CH₂CO₂H;CH₂CONH₂; —CONHCH₂CONH₂; 1,2-dihydroxyalkyl e.g. CH(OH)CH₂OH; CH₂CN;2-oxo-oxazolidin-5-yl; 2-oxo-oxazolidin-5-yl(C₁₋₄ alkyl); optionallysubstituted hydroxy. Most preferably R³ is hydrogen or hydroxy, and ifhydroxy, most preferably substituted in the 1-or 3-position. R³ in the3-position preferably has R stereochemistry.

When R³ and R⁶, R⁷, R⁸ or R⁹ together form a cyclic ester or amidelinkage, it is preferred that the resulting ring is 5-7 membered. It isfurther preferred that the group A or B which does not form the ester oramide linkage is CH₂.

When A is CH(OH) the R-stereochemistry is preferred.

Preferably A is NH, NCH₃, CH₂, CHOH, CH(NH₂), C(Me)(OH) or CH(Me).

Preferably B is CH₂ or CO.

Preferably n=0.

Preferably, when R^(v) and R^(w) are not a bond and n=1 or AB(CH₂)_(n)is NHCONH or NHCOO, AB(CH₂)_(n) and NR²R⁴ are cis.

Preferably, when R^(v) and R^(w) are not a bond and n=0 and AB is notNHCONH or NHCOO, AB(CH₂)_(n) and NR²R⁴ are trans.

Most preferably:

-   n is 0 and either A is CHOH, CH₂ and B is CH₂ or A is NH and B is    CO.

Preferably R¹¹ is hydrogen or (C₁₋₄)alkyl e.g. methyl, more preferablyhydrogen.

When R⁴ is CH₂R⁵ ₁, preferably R⁵, is (C₆₋₈)alkyl.

When R⁴ is a group —X^(1a)—X^(2a)—X^(3a)—X^(4a):

X^(1a) is preferably CH₂.

X^(2a) is preferably CH₂ or together with X^(3a) forms a CH═CH or C≡Cgroup.

X^(3a) is preferably CH₂, O, S or NH, or together with X^(2a) forms aCH═CH or C≡C group.

Preferred linker groups —X^(1a)—X^(2a)—X^(3a) include —(CH₂)₂—O—,—CH₂—CH═CH—, —(CH₂)₃—, —CH₂)₂—NH— or —CH₂CONH—.

Monocyclic aromatic heterocyclic groups for X^(4a) include pyridyl,pyrazinyl, pyrimidinyl, triazolyl, tetrazolyl, thienyl, isoimidazolyl,thiazolyl, furanyl and imidazolyl, 2H-pyridazone, 1H-pyrid-2-one.Preferred aromatic heterocyclic groups include pyrid-2-yl, pyrid-3-yl,thiazole-2-yl, pyrimidin-2-yl, pyrimidin-5-yl and fur-2-yl.

Preferred substituents on heterocyclic X^(4a) include halo especiallyfluoro, trifluoromethyl and nitro.

Preferred substituents on phenyl X^(4a) include halo, especially fluoro,nitro, cyano, trifluoromethyl, methyl, methoxycarbonyl andmethylcarbonylamino.

Preferably X^(4a) is 2-pyridyl, 3-fluorophenyl, 3,5-difluorophenyl orthiazol-2-yl.

Preferably R⁴ is —U—R⁵ ₂.

The group —U— is preferably —CH₂—.

Preferably R⁵ ₂ is an aromatic heterocyclic ring (A) having 8-11 ringatoms including 2-4 heteroatoms of which at least one is N or NR¹³ inwhich preferably Y² contains 2-3 heteroatoms, one of which is S and 1-2are N, with one N bonded to X³.

Alternatively and preferably the heterocyclic ring (A) has ring (a)aromatic selected from optionally substituted benzo and pyrido and ring(b) non-aromatic and Y² has 3-5 atoms including a heteroatom bonded toX⁵ selected from O, S or NR¹³, where R¹³ is other than hydrogen, andNHCO bonded via N to X³, or O bonded to X³. Examples of rings (A)include optionally substituted:

(a) and (b) Aromatic

-   1H-pyrrolo[2,3-b]-pyridin-2-yl, 1H-pyrrolo[3,2-b]-pyridin-2-yl,    3H-imidazo[4,5-b]-pyrid-2-yl, 3H-quinazolin-4-one-2-yl,    benzimidazol-2-yl, benzo[1,2,3]-thiadiazol-5-yl,    benzo[1,2,5]-oxadiazol-5-yl, benzofur-2-yl, benzothiazol-2-yl,    benzo[b]thiophen-2-yl, benzoxazol-2-yl, chromen-4-one-3-yl,    imidazo[1,2-a]pyridin-2-yl, imidazo-[1,2-a]-pyrimidin-2-yl,    indol-2-yl, indol-6-yl, isoquinolin-3-yl, [1,8]-naphthyridine-3-yl,    oxazolo[4,5-b]-pyridin-2-yl, quinolin-2-yl, quinolin-3-yl,    quinoxalin-2-yl, indan-2-yl, naphthalen-2-yl,    1,3-dioxo-isoindol-2-yl, benzimidazol-2-yl, benzothiophen-2-yl,    1H-benzotriazol-5-yl, 1H-indol-5-yl, 3H-benzooxazol-2-one-6-yl,    3H-benzooxazol-2-thione-6-yl, 3H-benzothiazol-2-one-5-yl,    3H-quinazolin-4-one-2-yl, 3H-quinazolin-4-one-6-yl,    4-oxo-4H-pyrido[1,2-a]pyrinmidin-3-yl, benzo[1,2,3]thiadiazol-6-yl,    benzo[1,2,5]thiadiazol-5-yl, benzo[1,4]oxazin-2-one-3-yl,    benzothiazol-5-yl, benzothiazol-6-yl, cinnolin-3-yl,    imidazo[1,2-a]pyridazin-2-yl, imidazo[1,2-b]pyridazin-2-yl,    pyrazolo[1,5-a]pyrazin-2-yl, pyrazolo[1,5-a]pyridin-2-yl,    pyrazolo[1,5-a]pyrimidin-6-yl, pyrazolo[5,1-c][1,2,4]triazin-3-yl,    pyrido[1,2-a]pyrimdin-4-one-2-yl, pyrido[1,2-a]pyrimidin-4-one-3-yl,    quinazolin-2-yl, quinoxalin-6-yl,    thiazolo[3,2-a]pyrimidin-5-one-7-yl, thiazolo[5,4-b]pyridin-2-yl,    thieno[3,2-b]pyridin-6-yl, thiazolo[5,4-b]pyridin-6-yl,    4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl,    1-oxo-1,2-dihydro-isoquinolin-3-yl, thiazolo[4,5-b]pyridin-5-yl,    [1,2,3]thiadiazolo[5,4-b]pyridin-6-yl, 2H-isoquinolin-1-one-3-yl    (a) is non aromatic-   (2S)-2,3-dihydro-1H-indol-2-yl,    (2S)-2,3-dihydro-benzo[1,4]dioxine-2-yl, 3-(R,    S)-3,4-dihydro-2H-benzo[1,4]thiazin-3-yl,    3-(R)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl,    3-(S)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl,    2,3-dihydro-benzo[1,4]dioxan-2-yl,    3-substituted-3H-quinazolin-4-one-2-yl,-   (b) is non aromatic-   1,1,3-trioxo-1,2,3,4-tetrahydro-1 l⁶-benzo[1,4] thiazin-6-yl,    benzo[1,3]dioxol-5-yl, 4H-benzo[1,4]oxazin-3-one-6-yl,    2,3-dihydro-benzo[1,4]dioxin-6-yl,    2-oxo-2,3-dihydro-benzooxazol-6-yl, 4H-benzo[1,4]oxazin-3-one-6-yl    (3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl),    4H-benzo[1,4]thiazin-3-one-6-yl    (3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl),    4H-benzo[1,4]oxazin-3-one-7-yl,    4-oxo-2,3,4,5-tetrahydro-benzo[b][1,4]thiazepine-7-yl,    5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidin-6-yl,    benzo[1,3]dioxol-5-yl,    2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazin-7-yl,    2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]thiazin-7-yl,    3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl,    2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl,    2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl,    2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl,    6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidin-2-yl,    3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl,    2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazin-7-yl,    2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl,    6-oxo-6,7-dihydro-5H-8-thia-1,2,5-triaza-naphthalen-3-yl,    3,4-dihydro-2H-benzo[1,4]oxazin-6-yl,    3,4-dihydro-2H-benzo[1,4]oxazin-6-yl,    3-substituted-3H-benzooxazol-2-one-6-yl,    3-substituted-3H-benzooxazole-2-thione-6-yl,    3-substituted-3H-benzothiazol-2-one-6-yl,    2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazin-7-yl,    3,4-dihydro-2H-benzo[1,4]thiazin-6-yl,    3,4-dihydro-1H-quinolin-2-one-7-yl,    3,4-dihydro-1H-quinoxalin-2-one-7-yl,    6,7-dihydro-4H-pyrazolo[1,5-a]pyrimidin-5-one-2-yl,    5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl,    2-oxo-3,4-dihydro-1H-[1,8]naphthyridin-6-yl.

R¹³ is preferably H if in ring (a) or in addition (C₁₋₄)alkyl such asmethyl or isopropyl when in ring (b). More preferably, in ring (b) R¹³is H when NR¹³ is bonded to X³ and (C₁₋₄)alkyl when NR¹³ is bonded toX⁵.

R¹⁴ and R¹⁵ are preferably independently selected from hydrogen, halo,hydroxy, (C₁₋₄) alkyl, (C₁₋₄)alkoxy, trifluoromethoxy, nitro, cyano,aryl(C₁₋₄)alkoxy and (C₁₋₄)alkylsulphonyl.

More preferably R¹⁵ is hydrogen.

More preferably each R¹⁴ is selected from hydrogen, chloro, fluoro,hydroxy, methyl, methoxy, trifluoromethoxy, benzyloxy, nitro, cyano andmethylsulphonyl. Most preferably R¹⁴ is selected from hydrogen, hydroxy,fluorine or nitro. Preferably 0-3 groups R¹⁴ are substituents other thanhydrogen.

Most preferably R¹⁴ and R¹⁵ are each H.

Most preferred groups R⁵ ₂ include:

-   [1,2,3]thiadiazolo[5,4-b]pyridin-6-yl-   1H-Pyrrolo[2,3-b]pyridin-2-yl-   2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl-   2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl-   2,3-Dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl-   2,3-dihydro-benzo[1,4]-dioxin-6-yl-   2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl-   2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazin-7-yl-   3,4-dihydro-2H-benzo[1,4]oxazin-6-yl-   3-Methyl-2-oxo-2,3-dihydro-benzooxazol-6-yl-   3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl-   3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl-   3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl    (4H-benzo[1,4]thiazin-3-one-6-yl)-   4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl-   6-nitro-benzo[1,3]dioxol-5-yl-   7-fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4] oxazin-6-yl-   8-Hydroxy-1-oxo-1,2-dihydro-isoquinolin-3-yl 8-hydroxyquinolin-2-yl-   benzo[1,2,3]thiadiazol-5-yl-   benzo[1,2,5]thiadiazol-5-yl-   benzothiazol-5-yl-   thiazolo-[5,4-b]pyridin-6-yl-   3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl-   7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl-   7-fluoro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl-   2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]thiazin-7-yl-   especially-   benzo[1,2,5]thiadiazol-5-yl-   3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl    (4H-benzo[1,4]thiazin-3-one-6-yl)-   2,3-dihydro-benzo[1,4]dioxin-6-yl benzo[1,2,3]thiadiazol-5-yl-   3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl-   7-fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl-   2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazin-7-yl-   2,3-Dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl-   3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl-   [1,2,3]thiadiazolo[5,4-b]pyridin-6-yl-   3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl-   7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl-   7-fluoro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl-   2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]thiazin-7-yl-   most especially-   3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl-   3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl-   7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl-   7-fluoro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl-   2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]thiazin-7-yl.

When used herein, the term “alkyl” includes groups having straight andbranched chains, for instance, methyl, ethyl, n-propyl, iso-propyl,n-butyl, iso-butyl, sec-butyl, t-butyl, pentyl and hexyl. The term‘alkenyl’ should be interpreted accordingly.

Halo or halogen includes fluoro, chloro, bromo and iodo.

Haloalkyl moieties include 1-3 halogen atoms.

Unless otherwise defined, the term ‘heterocyclic’ as used hereinincludes aromatic and non-aromatic, single and fused, rings suitablycontaining up to four hetero-atoms in each ring selected from oxygen,nitrogen and sulphur, which rings may be unsubstituted or C-substitutedby, for example, up to three groups selected from (C₁₋₄)alkylthio; halo;carboxy(C₁₋₄)alkyl; halo(C₁₋₄)alkoxy; halo(C₁₋₄)alkyl; (C₁₋₄)alkyl;(C₂₋₄)alkenyl; (C₁₋₄)alkoxycarbonyl; formyl; (C₁₋₄)alkylcarbonyl;(C₂₋₄)alkenyloxycarbonyl; (C₂₋₄)alkenylcarbonyl; (C₁₋₄)alkylcarbonyloxy;(C₁₋₄)alkoxycarbonyl(C₁₋₄)alkyl; hydroxy; hydroxy(C₁₋₄)alkyl;mercapto(C₁₋₄)alkyl; (C₁₋₄)alkoxy; nitro; cyano; carboxy; amino oraminocarbonyl optionally substituted as for corresponding substituentsin R³; (C₁₋₄)alkylsulphonyl; (C₂₋₄)alkenylsulphonyl; or aminosulphonylwherein the amino group is optionally substituted by (C₁₋₄)alkyl or(C₂₋₄)alkenyl; optionally substituted aryl, aryl(C₁₋₄)alkyl oraryl(C₁₋₄)alkoxy and oxo groups. Each heterocyclic ring suitably hasfrom 4 to 7, preferably 5 or 6, ring atoms. A fused heterocyclic ringsystem may include carbocyclic rings and need include only oneheterocyclic ring. Compounds within the invention containing aheterocyclyl group may occur in two or more tautometric forms dependingon the nature of the heterocyclyl group; all such tautomeric forms areincluded within the scope of the invention.

Where an amino group forms part of a single or fused non-aromaticheterocyclic ring as defined above suitable optional substituents insuch substituted amino groups include H; trifluoromethyl; (C₁₋₄)alkyloptionally substituted by hydroxy, (C₁₋₆)alkoxy, (C₁₋₆)alkylthio, haloor trifluoromethyl; (C₂₋₄)alkenyl; aryl; aryl (C₁₋₄)alkyl;(C₁₋₄)alkoxycarbonyl; (C₁₋₄)alkylcarbonyl; formyl; (C₁₋₆)alkylsulphonyl;or aminocarbonyl wherein the amino group is optionally substituted by(C₁₋₄)alkoxycarbonyl, (C₁₋₄)alkylcarbonyl, (C₂₋₄)alkenyloxycarbonyl,(C₂₋₄)alkenylcarbonyl, (C₁₋₄)alkyl or (C₂₋₄)alkenyl and optionallyfurther substituted by (C₁₋₄)alkyl or (C₂₋₄)alkenyl.

When used herein the term ‘aryl’, includes phenyl and naphthyl, eachoptionally substituted with up to five, preferably up to three, groupsselected from(C₁₋₄)alkylthio; halo; carboxy(C₁₋₄)alkyl;halo(C₁₋₄)alkoxy; halo(C₁₋₄)alkyl; (C₁₋₄)alkyl; (C₂₋₄)alkenyl;(C₁₋₄)alkoxycarbonyl; formyl; (C₁₋₄)alkylcarbonyl;(C₂₋₄)alkenyloxycarbonyl; (C₂₋₄)alkenylcarbonyl; (C₁₋₄)alkylcarbonyloxy;(C₁₋₄)alkoxycarbonyl(C₁₋₄)alkyl; hydroxy, hydroxy(C₁₋₄)alkyl;mercapto(C₁₋₄)alkyl; (C₁₋₄)alkoxy; nitro; cyano, carboxy; amino oraminocarbonyl optionally substituted as for corresponding substituentsin R³; (C₁₋₄)alkylsulphonyl; (C₂₋₄)alkenylsulphonyl; or aminosulphonylwherein the amino group is optionally substituted by (C₁₋₄)allyl or(C₂₋₄)alkenyl; phenyl, phenyl(C₁₋₄)alkyl or phenyl(C₁₋₄)alkoxy.

The term ‘acyl’ includes (C₁₋₆)alkoxycarbonyl, formyl or (C₁₋₆)alkylcarbonyl groups.

Some of the compounds of this invention may be crystallised orrecrystallised from solvents such as aqueous and organic solvents. Insuch cases solvates may be formed. This invention includes within itsscope stoichiometric solvates including hydrates as well as compoundscontaining variable amounts of water that may be produced by processessuch as lyophilisation.

Since the compounds of formula (I) are intended for use inpharmaceutical compositions it will readily be understood that they areeach provided in substantially pure form, for example at least 60% pure,more suitably at least 75% pure and preferably at least 85%, especiallyat least 98% pure (% are on a weight for weight basis). Impurepreparations of the compounds may be used for preparing the more pureforms used in the pharmaceutical compositions; these less purepreparations of the compounds should contain at least 1%, more suitablyat least 5% and preferably from 10 to 59% of a compound of the formula(I) or pharmaceutically acceptable derivative thereof.

Pharmaceutically acceptable derivatives of the above-mentioned compoundsof formula (I) include the free base form or their acid addition orquaternary ammonium salts, for example their salts with mineral acidse.g. hydrochloric, hydrobromic, sulphuric nitric or phosphoric acids, ororganic acids, e.g. acetic, fumaric, succinic, maleic, citric, benzoic,p-toluenesulphonic, methanesulphonic, naphthalenesulphonic acid ortartaric acids. Compounds of formula (I) may also be prepared as theN-oxide. Compounds of formula (I) having a free carboxy group may alsobe prepared as an in vivo hydrolysable ester. The invention extends toall such derivatives.

Examples of suitable pharmaceutically acceptable in vivo hydrolysableester-forming groups include those forming esters which break downreadily in the human body to leave the parent acid or its salt. Suitablegroups of this type include those of part formulae (i), (ii), (iii),(iv) and (v):

wherein R^(a) is hydrogen, (C₁₋₆) alkyl, (C₃₋₇) cycloalkyl, methyl, orphenyl, R^(b) is (C₁₋₆) alkyl, (C₁₋₆) alkoxy, phenyl, benzyl, (C₃₋₇)cycloalkyl, (C₃₋₇) cycloalkyloxy, (C₁₋₆) alkyl (C₃₋₇) cycloalkyl,1-amino (C₁₋₆) allyl, or 1-(C₁₋₆ alkyl)amino (C₁₋₆) alkyl; or R^(a) andR^(b) together form a 1,2-phenylene group optionally substituted by oneor two methoxy groups; R^(c) represents (C₁₋₆) alkylene optionallysubstituted with a methyl or ethyl group and R^(d) and R^(e)independently represent (C₁₋₆) alkyl; R^(f) represents (C₁₋₆) alkyl;R^(g) represents hydrogen or phenyl optionally substituted by up tothree groups selected from halogen, (C₁₋₆) allyl, or (C₁₋₆) alkoxy; Q isoxygen or NH; R^(h) is hydrogen or (C₁₋₆) alkyl; R^(i) is hydrogen,(C₁₋₆) alkyl optionally substituted by halogen, (C₂₋₆) alkenyl, (C₁₋₆)alkoxycarbonyl, aryl or heteroaryl; or R^(h) and R^(i) together form(C₁₋₆) alkylene; R^(j) represents hydrogen, (C₁₋₆) alkyl or (C₁₋₆)alkoxycarbonyl; and R^(k) represents (C₁₋₈) alkyl, (C₁₋₈) alkoxy, (C₁₋₆)alkoxy(C₁₋₆)alkoxy or aryl.

Examples of suitable in vivo hydrolysable ester groups include, forexample, acyloxy(C₁₋₆)alkyl groups such as acetoxymethyl,pivaloyloxymethyl, α-acetoxyethyl, α-pivaloyloxyethyl,1-(cyclohexylcarbonyloxy)prop-1-yl, and (1-aminoethyl)carbonyloxymethyl;(C₁₋₆)alkoxycarbonyloxy(C₁₋₆)alkyl groups, such asethoxycarbonyloxymethyl, α-ethoxycarbonyloxyethyl andpropoxycarbonyloxyethyl; di(C₁₋₆)alkylamino(C₁₋₆)alkyl especiallydi(C₁₋₄)alkylamino(C₁₋₄)alkyl groups such as dimethylaminomethyl,dimethylaminoethyl, diethylaminomethyl or diethylaminoethyl;2-((C₁₋₆)alkoxycarbonyl)-2-(C₂₋₆)alkenyl groups such as2-(isobutoxycarbonyl)pent-2-enyl and 2-(ethoxycarbonyl)but-2-enyl;lactone groups such as phthalidyl and dimethoxyphthalidyl.

A further suitable pharmaceutically acceptable in vivo hydrolysableester-forming group is that of the formula:

wherein R^(k) is hydrogen, C₁₋₆ alkyl or phenyl.

R is preferably hydrogen.

Certain of the above-mentioned compounds of formula (I) may exist in theform of optical isomers, e.g. diastereoisomers and mixtures of isomersin all ratios, e.g. racemic mixtures. The invention includes all suchforms, in particular the pure isomeric forms. For examples the inventionincludes compound in which an A-B group CH(OH)—CH₂ is in either isomericconfiguration the R-isomer is preferred. The different isomeric formsmaybe separated or resolved one from the other by conventional methods,or any given isomer may be obtained by conventional synthetic methods orby stereospecific or asymmetric syntheses.

In a further aspect of the invention there is provided a process forpreparing compounds of formula (I), or a pharmaceutically acceptablederivative thereof, which process comprises reacting a compound offormula (IV) with a compound of formula (V):

wherein n is as defined in formula (I), Z^(1′), Z^(2′), Z^(3′), Z^(4′),Z^(5′), R^(1′) and R^(3′) are Z¹, Z², Z³, Z⁴, Z⁵, R¹ and R³ as definedin formula (I) or groups convertible thereto; R^(v) and R^(w) are asdefined in formula (I);

-   Q¹ is NR^(2′)R^(4′) or a group convertible thereto wherein R^(2′)    and R^(4′) are R² and R⁴ as defined in formula (I) or groups    convertible thereto and Q² is H or R^(3′) or Q¹ and Q² together form    an optionally protected oxo group;-   and X and Y may be the following combinations:-   (i) one of X and Y is CO₂R^(y) and the other is CH₂CO₂R^(x);-   (ii) X is CHR⁶R⁷ and Y is C(═O)R⁹;-   (iii) X is CR⁷═PR^(z) ₃ and Y is C(═O)R⁹;-   (iv) X is C(═O)R⁷ and Y is CR⁹═PR_(z) ₃;-   (v) one of Y and X is COW and the other is NHR^(11′), NCO or    NR11′COW;-   (vi) X is NHR^(11′) and Y is C(═O)R⁸ or X is C(═O)R⁶ and Y is    NHR^(11′);-   (vii) X is NHR^(11′) and Y is CR⁸R⁹W;-   (viii) X is W or OH and Y is CH₂OH;-   (ix) X is NHR^(11′) and Y is SO₂W;-   (x) one of X and Y is (CH₂)_(p)−W and the other is    (CH₂)_(q)NHR^(11′), (CH₂)_(q)OH, (CH₂)_(q)SH or (CH₂)_(q)SCOR^(x)    where p+q=1;-   (xi) one of X and Y is OH and the other is —CH═N₂;-   (xii) X is NCO and Y is OH or NH₂;-   (xiii) X is CR⁶R⁷SO₂W, A′COW, CR⁶═CH₂ or oxirane and Y is NHR^(2′);-   (xiv) X is W and Y is CONHR¹¹ or OCONH₂-   (xv) X is W and Y is —C≡CH followed by hydrogenation of the    intermediate —C≡C-group;-   in which W is a leaving group, e.g. halo, methanesulphonyloxy,    trifluoromethanesulphonyloxy or imidazolyl; R^(x) and R^(y) are    (C₁₋₆)alkyl; R^(z) is aryl or (C₁₋₆)alkyl; A′ and NR^(11′) are A and    NR¹¹ as defined in formula (I), or groups convertible thereto; and    oxirane is:-   wherein R⁶, R⁸ and R⁹ are as defined in formula (I);-   and thereafter optionally or as necessary converting Q¹ and Q² to    NR^(2′)R^(4′); converting A′, Z^(1′), Z^(2′), Z^(3′), Z^(4′),    Z^(5′), R^(1′), R^(2′), R^(3′), R^(4′) and NR^(11′)to A, Z¹, Z², Z³,    Z⁴, Z⁵, R¹, R², R³, R⁴ and NR^(11′); converting A-B to other A-B,    interconverting R^(v), R^(w), R¹, R², R³ and/or R⁴, and/or forming a    pharmaceutically acceptable derivative thereof.

Process variant (i) initially produces compounds of formula (I) whereinA-B is CO—CH₂ or CH₂—CO.

Process variant (ii) initially produces compounds of formula (I) whereinA-B is CR⁶R⁷—CR⁹OH.

Process variant (iii) and (iv) initially produce compounds of formula(I) wherein A-B is CR⁷═CR⁹.

Process variant (v) initially produces compounds of formula (I) whereA-B is CO—NR¹¹ or NR¹¹—CO.

Process variant (vi) initially produces compounds of formula (I) whereinA-B is NR¹¹—CHR⁸ or CHR⁶—NHR¹¹.

Process variant (vii) initially produces compounds of formula (I)wherein A-B is NR^(11′)—CR⁸R⁹.

Process variant (viii) initially produces compounds of formula (I)wherein A-B is O—CH₂.

Process variant (ix) initially produces compounds where AB is NR¹¹SO₂.

Process variant (x) initially produces compounds of formula (I) whereinone of A and B is CH₂ and the other is NHR¹¹, O or S.

Process variant (xi) initially-produces compounds of formula(I) whereinA-B is OCH₂ or CH₂O.

Process variant (xii) initially produces compounds where AB is NH—CO—NHor NH—CO—O.

Process variant (xiii) initially produces compounds where n is 0 and ABis CR⁶R⁷SO₂NR², A′—CONR² or CR⁶R⁷CH₂NR².

Process variant (xiv) produces compounds where AB is NR¹¹CO or NH—CO—O.

Process variant (xv) produces compounds where AB is —CH₂CH₂— or —CH═CH—.

In process variants (v) and (xiii) (second variant) the reaction is astandard amide or urea formation reaction involving e.g.:

-   1. Activation of a carboxylic acid (e.g. to an acid chloride, mixed    anhydride, active ester, O-acyl-isourea or other species), and    treatment with an amine (Ogliaruso, M. A.; Wolfe, J. F. in The    Chemistry of Functional Groups (Ed. Patai, S.) Suppl. B: The    Chemistry of Acid Derivatives, Pt. 1 (John Wiley and Sons, 1979), pp    442-8; Beckwith, A. L. J. in The Chemistry of Functional Groups (Ed.    Patai, S.) Suppl. B: The Chemistry of Amides (Ed. Zabricky, J) (John    Wiley and Sons, 1970), p 73 ff. The acid and amine are preferably    reacted in the presence of an activating agent such as    1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) or    1-hydroxybenzotriazole (HOBT) or    O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate (HATU); or-   2. The specific methods of:-   a. in situ conversion of an acid into the amine component by a    modified Curtius reaction procedure (Shioiri, T., Murata, M.,    Hamada, Y., Chem. Pharm. Bull. 1987, 35, 2698)-   b. in situ conversion of the acid component into the acid chloride    under neutral conditions (Villeneuve, G. B.; Chan, T. H.,    Tetrahedron. Lett. 1997, 38, 6489).

A′ may be, for example, protected hydroxymethylene.

The process variant (xiii) (third variant) is a standard additionreaction using methods well known to those skilled in the art. Theprocess is preferably carried out in a polar organic solvent e.g.acetonitrile in the presence of an organic base e.g. triethylamine.

In process variant (xiii) (fourth variant) the coupling may be effectedin acetonitrile at room temperature in the presence of one equivalent oflithium perchlorate as catalyst (general method of J. E. Chateauneuf etal, J. Org. Chem., 56, 5939-5942, 1991) or more preferably withytterbium triflate in dichloromethane. In some cases an elevatedtemperature such as 40-70° C. may be beneficial. Alternatively, thecompound of formula (V) may be treated with a base, such as oneequivalent of butyl lithium, and the resulting salt reacted with theoxirane in an inert solvent such as tetrahydrofuran, preferably at anelevated temperature such as 80° C. Use of a chiral epoxide will affordsingle diastereomers. Alternatively, mixtures of diastereomers may beseparated by preparative HPLC or by conventional resolution throughcrystallisation of salts formed from chiral acids.

The process variant (xii) is a standard urea or carbamate formationreaction from the reaction of an isocyanate with an amine or alcohol andis conducted by methods well known to those skilled in the art (forexample see March, 3; Advanced Organic Chemistry, Edition 3 (John Wileyand Sons, 1985), p802-3). The process is preferably carried out in apolar solvent such as N,N-dimethylformamide.

In process variant (i) the process is two step: firstly a condensationusing a base, preferably sodium hydride or alkoxide, sodamide, alkyllithium or lithium dialkylamide, preferably in an aprotic solvent e.g.ether, THF or benzene; secondly, hydrolysis using an inorganic acid,preferably HCl in aqueous organic solvent at 0-100° C. Analogous routesare described in DE330945, EP31753, EP53964 and H. Sargent, J. Am. Chem.Soc. 68, 2688-2692 (1946). Similar Claisen methodology is described inSoszko et. al., Pr.Kom.Mat. Przyr.Poznan.Tow.Przyj.Nauk., (1962), 10,15.

In process variant (ii) the reaction is carried out in the presence of abase, preferably organometallic or metal hydride e.g. NaH, lithiumdiisopropylamide or NaOEt, preferably in an aprotic solvent, preferablyTHF, ether or benzene at −78 to 25° C. (analogous process in Gutswilleret at. (1978) J. Am. Chem. Soc. 100, 576).

In process variants (iii) and (iv) if a base is used it is preferablyNaH, KH, an alkyl lithium e.g. BuLi, a metal alkoxide e.g. NaOEt,sodamide or lithium dialkylamide e.g. diisopropylamide. An analogousmethod is described in U.S. Pat. No. 3,989,691 and M. Gates et. al.(1970) J. Amer.Chem.Soc., 92, 205, as well as Taylor et al. (1972) JACS94, 6218.

In process variant (vi) the reaction is a standard reductive alkylationusing, e.g., sodium borohydride or sodium triacetoxyborohydride(Gribble, G. W. in Encyclopedia of Reagents for Organic Synthesis (Ed.Paquette, L. A.) (John Wiley and Sons, 1995), p 4649).

The process variant (vii) is a standard alkylation reaction well knownto those skilled in the art, for example where an alcohol or amine istreated with an alkyl halide in the presence of a base (for example seeMarch, J; Advanced Organic Chemistry, Edition 3 (John Wiley and Sons,1985), p364-366 and p342-343). The process is preferably carried out ina polar solvent such as N,N-dimethylformamide

In process variant (xiii) (first variant) the reaction is a standardsulphonamide formation reaction well known to those skilled in the art.This may be e.g. the reaction of a sulphonyl halide with an amine.

In process variant (viii) where X is W such as halogen,methanesulphonyloxy or trifluoromethanesulphonyloxy, the hydroxy groupin Y is preferably converted to an OM group where M is an alkali metalby treatment of an alcohol with a base. The base is preferably inorganicsuch as NaH, lithium diisopropylamide or sodium. Where X is OH, thehydroxy group in Y is activated under Mitsunobu conditions (Fletcheret.al. J Chem Soc. (1995), 623). Alternatively the X═O and Y═CH₂OHgroups can be reacted directly by activation with1,3-dicyclohexylcarbodiimide (DCC) (Chem. Berichte 1962, 95, 2997 orAngewante Chemie 1963 75, 377).

In process variant (ix) the reaction is conducted in the presence of anorganic base such as triethylamine or pyridine such as described byFuhrman et.al., J. Amer. Chem. Soc.; 67, 1245, 1945. The X═NR¹¹′SO₂W orY═SO₂W intermediates can be formed from the requisite amine e.g. byreaction with SO₂Cl₂ analogously to the procedure described by the sameauthors Fuhrman et. al., J. Amer. Chem. Soc.; 67, 1245, 1945.

In process variant (x) where one of X and Y contains NHR¹¹ the leavinggroup W is halogen and the reaction is a standard amine formationreaction such as direct alkylation described in (Malpass, J. R., inComprehensive Organic Chemistry, Vol. 2 (Ed. Sutherland, I. O.), p 4ff.) or aromatic nucleophilic displacement reactions (see referencescited in Comprehensive Organic Chemistry, Vol. 6, p 946-947 (reactionindex); Smith, D. M. in Comprehensive Organic Chemistry, Vol. 4 (Ed.Sammes, P. G.) p 20 ff.). This is analogous to the methods described inGB 1177849.

In process variant (x) where one of X and Y contains OH or SH, this ispreferably converted to an OM or SM group where M is an alkali metal bytreatment of an alcohol, thiol or thioacetate with a base. The base ispreferably inorganic such as NaH, lithium diisopropylamide or sodium,or, for SH, metal alkoxide such as sodium methoxide. The X/Y groupcontaining the thioacetate SCOR^(X) is prepared by treatment of analcohol or alkyl halide with thioacetic acid or a salt thereof underMitsunobu conditions. The leaving group V is a halogen. The reaction maybe carried out as described in Chapman et.al., J. Chem Soc., (1956),1563, Gilligan et. al., J. Med. Chem., (1992), 35, 4344, Aloup et. al.,J. Med. Chem. (1987), 30, 24, Gilman et al., J.A.C.S. (1949), 71, 3667and Clinton et al., J.A.C.S. (1948), 70,491, Barluenga et al., J. Org.Chem. (1987) 52, 5190. Alternatively where X is OH and Y is CH₂V, V is ahydroxy group activated under Mitsunobu conditions Fletcher et.al. JChem Soc. (1995), 623).

In process variant (xi) the reaction is as described in den Hertzog et.al., recl.Trav. Chim. Pays-Bas, (1950), 69, 700.

In process variant (xiv) the leaving group W is preferably chloro, bromoor trifluoromethylsulphonyl and the reaction is the palladium catalysedprocess known as the “Buchwald” reaction (J. Yin and S. L. Buchwald,Org.Lett., 2000, 2, 1101).

In process variant (xv) coupling of the acetylene compound (V) with thecompound (IV) is accomplished using standard Pd-mediated chemistry, forexample using Pd(Ph₃P)₂Cl₂ as the catalyst along with the addition ofCuI in a mixture of triethylamine and dimethylformamide. Hydrogenationof the intermediate —C≡C— group is carried out conventionally over asuitable catalyst eg Pd/C, either partially to —CH═CH— or fully to—CH₂—CH₂—.

Reduction of a carbonyl group A or B to CHOH can be readily accomplishedusing reducing agents well known to those skilled in the art, e.g.sodium borohydride in aqueous ethanol or lithium aluminium hydride inethereal solution. This is analogous to methods described in EP53964,U.S. Pat. No. 384556 and J. Gutzwiller et al, J. Amer. Chem. Soc., 1978,100, 576.

The carbonyl group A or B may be reduced to CH₂ by treatment with areducing agent such as hydrazine in ethylene glycol, at e.g. 130-160°C., in the presence of potassium hydroxide.

Reaction of a carbonyl group A or B with an organometallic reagentyields a group where R⁶ or R⁸ is OH and R⁷ or R⁹ is alkyl.

A hydroxy group on A or B may be oxidised to a carbonyl group byoxidants well known to those skilled in the art, for example, manganesedioxide, pyridinium chlorochromate or pyridinium dichromate.

A hydroxyalkyl A-B group CHR⁷CR⁹OH or CR⁷(OH)CHR⁹ may be dehydrated togive the group CR⁷═CR⁹ by treatment with an acid anhydride such asacetic anhydride.

Methods for conversion of CR⁷═CR⁹ by reduction to CHR⁷CHR⁹ are wellknown to those skilled in the art, for example using hydrogenation overpalladium on carbon as catalyst. Methods for conversion of CR⁷═CR⁹ togive the A-B group CR⁷(OH)CHR⁹ or CHR⁷CR⁹OH are well known to thoseskilled in the art for example by epoxidation and subsequent reductionby metal hydrides, hydration, hydroboration or oxymercuration. WhereR^(v) and R^(w) together represent a bond it will be appreciated thatsuch conversions may be inappropriate.

An amide carbonyl group may be reduced to the corresponding amine usinga reducing agent such as lithium aluminium hydride.

A hydroxy group in A or B may be converted to azido by activation anddisplacement e.g. under Mitsunobu conditions using hydrazoic acid or bytreatment with diphenylphosphorylazide and base, and the azido group inturn may be reduced to amino by hydrogenation.

An example of a group Q¹ convertible to NR² R⁴ is NR^(2′)R^(4′) orhalogen. Halogen may be displaced by an amine HNR^(2′)R^(4′) by aconventional alkylation.

When Q¹ Q² together form a protected oxo group this may be an acetalsuch as ethylenedioxy which can subsequently be removed by acidtreatment to give a compound of formula (VI):

wherein the variables are as described for formula (I)

Intermediates of formula (VI) are novel and as such form part of theinvention.

The ketone of formula (VI) is reacted with an amine HNR^(2′)R^(4′) byconventional reductive alkylation as described above for process variant(x).

Other novel intermediates of the invention are compounds of formula(VII):

wherein the variables are as described for formula (I).

Examples of groups Z^(1′), Z^(2′), Z^(3′), Z^(4′), Z^(5′), are CR^(1a′)where R^(1a′) is a group convertible to R^(1a). Z^(1′), Z^(2′), Z^(3′),Z^(4′) and Z^(5′) are preferably Z¹, Z², Z³, Z⁴ and Z⁵.

R^(1a′), R^(1′) and R^(2′) are preferably R^(1a), R¹ and R². R^(1′) ispreferably methoxy. R^(2′) is preferably hydrogen. R^(3′) is R³ or morepreferably hydrogen, vinyl, alkoxycarbonyl or carboxy. R^(4′) is R⁴ ormore preferably H or an N-protecting group such as t-butoxycarbonyl,benzyloxycarbonyl or 9-fluorenylmethyloxycarbonyl.

Conversions of R^(1a′), R^(1′), R^(2′), R^(3′) and R^(4′) andinterconversions of R^(1a), R¹, R², R³ and R⁴ are conventional. Incompounds which contain an optionally substituted hydroxy group,suitable conventional hydroxy protecting groups which may be removedwithout disrupting the remainder of the molecule include acyl andalkylsilyl groups. N protecting groups are removed by conventionalmethods.

For example R^(1′) methoxy is convertible to R^(1′) hydroxy by treatmentwith lithium and diphenylphosphine (general method described in Irelandet. al. (1973) J.Amer.Chem.Soc., 7829) or HBr. Alkylation of the hydroxygroup with a suitable alkyl derivative bearing a leaving group such ashalide and a protected amino, piperidyl, amidino or guanidino group orgroup convertible thereto, yields, after conversion/deprotection, R¹alkoxy substituted by optionally N-substituted amino, piperidyl,guanidino or amidino.

R³ alkenyl is convertible to hydroxyalkyl by hydroboration using asuitable reagent such as 9-borabicyclo[3.3.1]nonane, epoxidation andreduction or oxymercuration.

R³ 1,2-dihydroxy can be prepared from R^(3′) alkenyl using osmiumtetroxide or other reagents well known to those skilled in the art (seeAdvanced Organic Chemistry (Ed. March, J) (John Wiley and Sons, 1985), p732-737 and refs. cited therein) or epoxidation followed by hydrolysis(see Advanced Organic Chemistry (Ed. March, J.) (John Wiley and Sons,1985), p 332, 333 and refs. cited therein).

R³ vinyl can be chain extended by standard homologation e.g byconversion to hydroxyethyl followed by oxidation to the aldehyde whichis then subjected to a Wittig reaction.

Opening an epoxide R^(3′) group with cyanide anion yields a CH(OH)—CH₂CNgroup.

Opening an epoxide-containing R^(3′) group with azide anion yields anazide derivative which can be reduced to the amine. Conversion of theamine to a carbamate is followed by ring closure with base to give the2-oxo-oxazolidinyl containing R³ group.

Substituents on R³ alkyl or alkenyl may be interconverted byconventional methods, for example hydroxy may be derivatised byesterification, acylation or etherification. Hydroxy groups may beconverted to halogen, thiol, alkylthio, azido, alkylcarbonyl, amino,aminocarbonyl, oxo, alkylsulphonyl, alkenylsulphonyl or aminosulphonylby conversion to a leaving group and substitution by the required group,hydrolysis or oxidation as appropriate or reaction with an activatedacid, isocyanate or alkoxyisocyanate. Primary and secondary hydroxygroups can be oxidised to an aldehyde or ketone respectively andalkyated with a suitable agent such as an organometallic reagent to givea secondary or tertiary alcohol as appropriate. A carboxylate group maybe converted to an hydroxymethyl group by reduction of an ester of thisacid with a suitable reducing agent such as lithium aluminium hydride.

Substituted 2-oxo-oxazolidinyl containing R³ groups may be prepared fromthe corresponding aldehyde by conventional reaction with a glycine anionequivalent, followed by cyclisation of the resulting amino alcohol (MGrauert et al, Ann Chem (1985) 1817, Rozenberg et al, Angew Chem Int EdEngl (1994) 33(1) 91). The resulting 2-oxo-oxazolidinyl group contains acarboxy group which can be converted to other R¹⁰ groups by standardprocedures.

Carboxy groups within R³ may be prepared by Jones' oxidation of thecorresponding alcohols CH₂OH using chromic acid and sulphuric acid inwater/methanol E. R. H. Jones et al, J.C.S. 1946, 39). Other oxidisingagents may be used for this transformation such as sodium periodatecatalysed by ruthenium trichloride (G. F. Tutwiler et al, J.Med.Chem.,1987, 30(6), 1094), chromium trioxide-pyridine (G. Just et al, Synth.Commun. 1979, 9(7), 613), potassium permanganate (D. E. Reedich et al,J. Org. Chem., 1985, 50(19), 3535, and pyridinium chlorochromate (D.Askin et al, Tetrahedron Letters, 1988, 29(3), 277.

The carboxy group may alternatively be formed in a two stage process,with an initial oxidation of the alcohol to the corresponding aldehydeusing for instance dimethyl sulphoxide activated with oxalyl chloride(N.Cohen et al, J. Am. Chem. Soc., 1983, 105, 3661) ordicyclohexylcarbodiimide R. M. Wengler, Angew. Chim. Int. Ed. Eng.,1985, 24(2), 77), or oxidation with tetrapropylammonium perruthenate(Ley et al, J. Chem.Soc. Chem Commun., 1987, 1625). The aldehyde maythen be separately oxidised to the corresponding acid using oxidisingagents such as silver (II) oxide (R.Grigg et at, J. Chem. Soc. Perkin1,1983, 1929), potassium permanganate (A. Zurcher, Helv. Chim. Acta.,1987, 70 (7), 1937), sodium periodate catalysed by ruthenium trichloride(T. Sakata et al, Bull. Chem. Soc. Jpn., 1988, 61(6), 2025), pyridiniumchlorochromate (R. S. Reddy et al, Synth. Commun., 1988, 18(51), 545) orchromium trioxide (R. M. Coates et al, J. Am. Chem. Soc., 1982, 104,2198).

An R³ CO₂H group may also be prepared from oxidative cleavage of thecorresponding diol, CH(OH)CH₂OH, using sodium periodate catalysed byruthenium trichloride with an acetonitrile-carbontetrachloride-watersolvent system (V. S. Martin et al, Tetrahedron Letters, 1988, 29(22),2701).

R³ groups containing a cyano or carboxy group may also be prepared byconversion of an alcohol to a suitable leaving group such as thecorresponding tosylate by reaction with para-toluenesulphonyl chloride(M. R. Bell, J. Med. Chem., 1970, 13, 389), or the iodide usingtriphenylphosphine, iodine, and imidazole (G. Lange, Synth. Commun.,1990, 20, 1473). The second stage is the displacement of the leavinggroup with cyanide anion (L. A. Paquette et al, J. Org. Chem., 1979, 44(25), 4603; P. A. Grieco et al, J. Org. Chem., 1988, 53 (16), 3658).Finally acidic hydrolysis of the nitrile group gives the desired acids(H. Rosemeyer et al, Heterocycles, 1985, 23 (10), 2669). The hydrolysismay also be carried out with base e.g. potassium hydroxide (H. Rapoport,J. Org. Chem., 1958, 23, 248) or enzymatically (T. Beard et al,Tetrahedron Asymmetry, 1993, 4 (6), 1085).

Other functional groups in R³ may be obtained by conventionalconversions of carboxy or cyano groups.

Tetrazoles are conveniently prepared by reaction of sodium azide withthe cyano group (e.g. F. Thomas et al, Bioorg. Med. Chem. Lett., 1996, 6(6), 631; K. Kubo et al, J. Med. Chem., 1993, 36, 2182) or by reactionof azidotri-n-butyl stannane with the cyano group followed by acidichydrolysis (P. L. Ornstein, J. Org. Chem., 1994,59,7682 and J. Med.Chem, 1996,39 (11), 2219).

The 3-hydroxy-3-cyclobutene-1,2-dion-4-yl group (e.g. R. M. Soll,Bioorg. Med. Chem. Lett., 1993, 3 (4), 757 and W. A. Kinney, J. Med.Chem., 1992, 35 (25), 4720) can be prepared by the followingsequence:—(1) a compound where R³ is (CH₂)_(n)CHO (n=0, 1, 2) is treatedwith triethylamine, carbon tetrabromide/triphenylphosphine to giveinitially (CH₂)_(n)CH═CBr₂; (2) dehydrobromination of this intermediateto give the corresponding bromoethyne derivative (CH₂)_(n)C≡CBr (forthis 2 stage sequence see D. Grandjean et al, Tetrahedron Letters, 1994,35 (21), 3529); (3) palladium-catalysed coupling of the bromoethyne with4-(1-methylethoxy)-3-(tri-n-butylstannyl)cyclobut-3-ene-1,2-dione(Liebeskind et al, J. Org. Chem., 1990, 55, 5359); (4) reduction of theethyne moity to —CH2CH2— under standard conditions of hydrogen andpalladium on charcoal catalysis(see Howard et al, Tetrahedron, 1980, 36,171); and finally (4) acidic hydrolysis of the methylethoxyester togenerate the corresponding 3-hydroxy-3-cyclobutene-1,2-dione group (R.M. Soll, Bioorg. Med. Chem. Lett., 1993, 3 (4), 757).

The tetrazol-5-ylaminocarbonyl group may be prepared from thecorresponding carboxylic acid and 2-aminotetrazole by dehydration withstandard peptide coupling agents such as 1,1′-carbonyldiimidazole (P. L.Ornstein et al, J. Med Chem, 1996, 39 (11), 2232).

The alkyl and alkenyl-sulphonylcarboxamides are similarly prepared fromthe corresponding carboxylic acid and the alkyl- or alkenyl-sulphonamideby dehydration with standard peptide coupling agents such as1,1′-carbonyldiimidazole (P. L. Ornstein et al, J.Med.Chem., 1996, 39(11), 2232).

The hydroxamic acid groups are prepared from the corresponding acids bystandard amide coupling reactions eg N. R. Patel et al, Tetrahedron,1987, 43 (22), 5375

2,4-thiazolidinedione groups may prepared from the aldehydes bycondensation with 2,4-thiazolidinedione and subsequent removal of theolefinic double bond by hydrogenation.

The preparation of 5-oxo-1,2,4-oxadiazoles from nitrites is described byY. Kohara et al, Bioorg. Med. Chem. Lett., 1995, 5(17), 1903.

1,2,4-triazol-5-yl groups may be prepared from the corresponding nitrileby reaction with an alcohol under acid conditions followed by reactionwith hydrazine and then an R¹⁰-substituted activated carboxylic acid(see J B Polya in ‘Comprehensive Heterocyclic Chemistry’ Edition 1 p762,Ed A R Katritzky and C W Rees, Pergamon Press, Oxford 1984 and J. J.Ares et al, J. Heterocyclic Chem., 1991, 28(5), 1197).

The cyclohexylamine or cyclohexenylamine NH₂ is converted to NR²R⁴ byconventional means such as amide or sulphonamide formation with an acylderivative for compounds where U or X^(1a) is CO or SO₂ or, where R⁴ isCH₂R⁵, or U or X^(1a) is CH₂, by alkylation with an alkyl halide orother alkyl derivative R⁴-W in the presence of base, acylation/reductionor reductive alkylation with an aldehyde.

Where one of R³ and R⁶, R⁷, R⁸ or R⁹ contains a carboxy group and theother contains a hydroxy or amino group they may together form a cyclicester or amide linkage. This linkage may form spontaneously duringcoupling of the compounds of formulae (IV) and (V) or in the presence ofstandard peptide coupling agents.

It will be appreciated that under certain circumstances interconvertionsmay interfere, for example, hydroxy groups in A or B and the cyclohexyl-or cyclohexenylamine will require protection e.g. as a carboxy- orsilyl-ester group for hydroxy and as an acyl derivative for nitrogen,during conversion of R^(1a′), R^(1′), R^(2′), R^(3′) or R^(4′), orduring the coupling of the compounds of formulae (IV) and (V).

Compounds of formulae (I) and (V) are known compounds, (see for exampleSmith et al, J. Amer. Chem. Soc., 1946, 68, 1301) or preparedanalogously, see for example the references cited above.

Compounds of formula (IV) where X is CR⁶R⁷SO₂W may be prepared by aroute analogous to that of Ahmed El Hadri et al, J. Heterocyclic Chem.,1993, 30(3), 631. Thus compounds of formula (IV) where X is CH₂SO₂OH maybe prepared by reacting the corresponding 4-methyl compound withN-bromosuccinimide, followed by treatment with sodium sulfite. Theleaving group W may be converted to another leaving group W, e.g. ahalogen group, by conventional methods.

The isocyanate of formula (IV) may be prepared conventionally from a4-amino derivative such as 4-amino-quinoline, and phosgene, or phosgeneequivalent (eg triphosgene) or it may be prepared more conveniently froma 4-carboxylic acid by a “one-pot” Curtius Reaction with diphenylphosphoryl azide (DPPA) [see T. Shiori et al. Chem. Pharm. Bull. 35,2698-2704 (1987)].

The 4-amino derivatives are commercially available or may be prepared byconventional procedures from a corresponding 4-chloro derivative bytreatment with ammonia (O. G. Backeberg et. al., J. Chem Soc., 381,1942) or propylamine hydrochloride (R. Radinov et. al., Synthesis, 886,1986).

4-Alkenyl compounds of formula (IV) may be prepared by conventionalprocedures from a corresponding 4-halogeno-derivative by e.g. a Hecksynthesis as described in e.g. Organic Reactions, 1982, 27, 345.

4-Halogeno derivatives of compounds of formula (IV) are commerciallyavailable, or may be prepared by methods known to those skilled in theart. A 4-chloroquinoline is prepared from the correspondingquinolin-4-one by reaction with phosphorus oxychloride (POCl₃) orphosphorus pentachloride, PCl₅ A-4-bromo-substituent may be preparedfrom the quinolin- or naphthyridin-4-one by reaction with phosphorustribromide (PBr3) in DMF. A 4-chloroquinazoline is prepared from thecorresponding quinazolin-4-one by reaction with phosphorus oxychloride(POCl₃) or phosphorus pentachloride, PCl₅. A quinazolinone andquinazolines may be prepared by standard routes as described by T. A.Williamson in Heterocyclic Compounds, 6, 324 (1957) Ed. R. C.Elderfield.

Activated carboxy derivatives X=A′COW of formula (IV) may be preparedfrom X=A′CO₂H derivatives in turn prepared from CO₂H derivatives byconventional methods such as homologation.

4-Carboxy derivatives of compounds of formula (IV) are commerciallyavailable or may be prepared by conventional procedures for preparationof carboxy heteroaromatics well known to those skilled in the art. Forexample, quinazolines may be prepared by standard routes as described byT. A. Williamson in Heterocyclic Compounds, 6, 324 (1957) Ed. R. C.Elderfield. These 4-carboxy derivatives may be activated by conventionalmeans, e.g. by conversion to an acyl halide or anhydride.

4-Carboxy derivatives such as esters may be reduced to hydroxymethylderivatives with for example lithium aluminium hydride. Reaction withmesyl chloride and triethylamine would give the mesylate derivative. Adiazo compound (X is —CH═N₂) may be prepared from the 4-carboxaldehydevia the tosyl hydrazone. The 4-carboxaldehyde may be obtained from formthe acid by standard procedures well known to those skilled in the art.

A 4-oxirane derivative of compounds of formula (IV) is convenientlyprepared from the 4-carboxylic acid by first conversion to the acidchloride with oxalyl chloride and then reaction withtrimethylsilyldiazomethane to give the diazoketone derivative.Subsequent reaction with 5M hydrochloric acid gives thechloromethylketone. Reduction with sodium borohydride in aqueousmethanol gives the chlorohydrin which undergoes ring closure to affordthe epoxide on treatment with base, e.g. potassium hydroxide inethanol-tetrahydrofuran.

Alternatively and preferably, 4-oxirane derivatives can be prepared frombromomethyl ketones which can be obtained from 4-hydroxy compounds byother routes well known to those skilled in the art. For example,hydroxy compounds can be converted to the corresponding4-trifluoromethanesulphonates by reaction with trifluoromethanesulphonicanhydride under standard conditions (see K. Ritter, Synthesis, 1993,735). Conversion into the corresponding butyloxyvinyl ethers can beachieved by a Heck reaction with butyl vinyl ether under palladiumcatalysis according to the procedure of W. Cabri et al, J. Org. Chem,1992, 57 (5), 1481. (Alternatively, the equivalent intermediates can beattained by Stille coupling of the trifluoromethanesulphonates or theanalaogous chloro derivatives with (1-ethoxyvinyl)tributyl tin, (T. R.Kelly, J. Org. Chem., 1996, 61, 4623.) The alkyloxyvinyl ethers are thenconverted into the corresponding bromomethylketones by treatment withN-bromosuccinimide in aqueous tetrahydrofuran in a similar manner to theprocedures of J. F. W. Keana, J. Org. Chem., 1983, 48, 3621 and T. R.Kelly, J. Org. Chem., 1996, 61, 4623.

The 4-hydroxyderivatives can be prepared from an aminoaromatic byreaction with methylpropiolate and subsequent cyclisation, analogous tothe method described in N. E. Heindel et al, J. Het. Chem., 1969, 6, 77.For example, 5-amino-2-methoxy pyridine can be converted to4-hydroxy-6-methoxy-[1,5]naphthyridine using this method.

If a chiral reducing agent such as (+) or(−)-B-chlorodiisopinocamphenylborane [‘DIP-chloride’] is substituted forsodium borohydride, the prochiral chloromethylketone is converted intothe chiral chlorohydrin with ee values generally 85-95% [see C. Bohm etal, Chem. Ber. 125, 1169-1190, (1992)]. Recrystallisation of the chiralepoxide gives material in the mother liquor with enhanced optical purity(typically ee 95%).

The (R)-epoxide, when reacted with an amine derivative givesethanolamine compounds as single diastereomers with (R)-stereochemistryat the benzylic position.

Alternatively, the epoxide may be prepared from the 4-carboxaldehyde bya Wittig approach using trimethylsulfonium iodide [see G. A. Epling andK-Y Lin, J. Het. Chem., 1987, 24, 853-857], or by epoxidation of a4-vinyl derivative.

Pyridazines may be prepared by routes analogous to those described inComprehensive Heterocyclic Chemistry, Volume 3, Ed A. J. Boulton and A.McKillop and napthyridines may be prepared by routes analogous to thosedescribed in Comprehensive Heterocyclic Chemistry, Volume 2, Ed A. J.Boulton and A. McKillop.

4-Hydroxy-1,5-naphthyridines can be prepared from 3-aminopyridinederivatives by reaction with diethyl ethoxymethylene malonate to producethe 4-hydroxy-3-carboxylic acid ester derivative with subsequenthydrolysis to the acid, followed by thermal decarboxylation in quinoline(as for example described for 4-Hydroxy-[1,5]naphthyridine-3-carboxylicacid, J. T. Adams et al., J. Amer. Chem.Soc., 1946, 68, 1317). A4-hydroxy-[1,5]naphthyridine can be converted to the 4-chloro derivativeby heating in phosphorus oxychloride, or to the 4-methanesulphonyloxy or4-trifluoromethanesulphonyloxy derivative by reaction withmethanesulphonyl chloride or trifluoromethanesulphonic anhydride,respectively, in the presence of an organic base. A 4-amino1,5-naphthyridine can be obtained from the 4-chloro,4-methanesulphonyloxy or 4-trifluoromethanesulphonyloxy derivative byreaction with n-propylamine in pyridine.

Similarly, 6-methoxy-1,5-naphthyridine derivatives can be prepared from3-amino-6-methoxypyridine.

1,5-Naphthyridines may be prepared by other methods well known to thoseskilled in the art (for examples see P. A. Lowe in “ComprehensiveHeterocyclic Chemistry” Volume 2, p581-627, Ed A. R. Katritzky and C. W.Rees, Pergamon Press, Oxford, 1984).

The 4-hydroxy and 4-amino-cinnolines may be prepared following methodswell known to those skilled in the art [see A. R. Osborn and K.Schofield, J. Chem. Soc. 2100 (1955)]. For example, a2-aminoacetophenone is diazotised with sodium nitrite and acid toproduce the 4-hydroxycinnoline with conversion to chloro and aminoderivatives as described for 1,5-naphthyridines.

The compounds of formula (V) are either commercially available or may beprepared by conventional methods.

For compounds of formula (V), where Y is NHR^(11′) suitable amines maybe prepared from the corresponding 4-substituted cyclohexyl- orcyclohexenyl acid or alcohol. In a first instance, an N-protectedcyclohexyl- or cyclohexenyl amine containing an acid bearingsubstituent, can undergo a Curtius rearrangement and the intermediateisocyanate can be converted to a carbamate by reaction with an alcohol.Conversion to the amine may be achieved by standard methods well knownto those skilled in the art used for amine protecting group removal. Forexample, an acid substituted N-protected cyclohexyl- or cyclohexenylamine can undergo a Curtius rearrangement e.g. on treatment withdiphenylphosphoryl azide and heating, and the intermediate isocyanatereacts in the presence of 2-trimethylsilylethanol to give thetrimethylsilylethylcarbamate (T. L. Capson & C. D. Poulter, TetrahedronLett., 1984, 25, 3515). This undergoes cleavage on treatment withtetrabutylammonium fluoride to give the 4-amine substituted N-protectedcompound of formula (V). Alternatively, an acid group (CH₂)_(n−1)CO₂Hmay be converted to (CH₂)_(n)NHR¹¹ by reaction with an activating agentsuch as isobutyl chloroformate followed by an amine R^(11′)NH₂ and theresulting amide reduced with a reducing agent such as LiAlH₄.

In a second instance, an N-protected cyclohexyl- or cyclohexenyl aminecontaining an alcohol bearing substituent undergoes a Mitsunobu reaction(for example as reviewed in Mitsunobu, Synthesis, (1981), 1), forexample with succinimide in the presence of diethyl azodicarboxylate andtriphenylphosphine to give the phthalimidoethylcyclohexyl- orcyclohexenyl amine. Removal of the phthaloyl group, for example bytreatment with methylhydrazine, gives the amine of formula (V).

Compounds of formula (V) where n=1 may be prepared from the compoundwhere n=0 by homologation eg starting from a compound of formula (V)where Y═CO₂H.

Compounds of formula (V) with a —C≡CH group may be prepared from theketone treated with trimethylsilylacetylene and n-butyl lithium indimethylformamide at low temperature followed by removal of thetrimethylsilyl group with potassium carbonate in methanol or a fluoridesource such as KF or tetrabutylammonium fluoride.

Compounds of formula (V) with a —CONHR¹¹ group may be prepared from thecorresponding nitrile by partial hydrolysis with with concentratedmineral acid at ambient temperature, such as concentrated hydrochloricacid (M. Brown et al, J. Med. Chem., 1999, 42, (9), 1537) or withconcentrated sulphuric acid (F. Macias et al Tetrahedron, 2000, 56,(21), 3409).

Compounds of formula (V) with a —OCONH₂ group may be prepared from thecorresponding alcohol by reaction with phosgene followed by ammonia.

Compounds of formula (V) substituted by R³ at the 1- or 4-position maybe prepared from a 1-keto derivative via a cyanohydrin reaction withsodium cyanide/hydrochloric acid in an ether/water two phase system (J.Marco et al Tetrahedron, 1999, 55, (24), 7625), or usingtrimethylsilylcyanide and zinc iodide catalysis in dichloromethane (A.Abad et al, J. Chem. Soc., Perkin 1, 1996, 17, 2193), followed byhydrolysis by heating in concentrated hydrochloric acid to give theα-hydroxy acid (Compound(V), Y═CO₂H, n=0, R^(3′)═OH and Q¹ isNR^(2′)R^(4′)) or partial hydrolysis to the carboxamide —CONH₂ asdescribed above. In examples where there is trimethylsilyl protection ofthe alcohol, this is removed under the acidic conditions of cyanidehydrolysis. It will be appreciated that the amine protecting group egN-carboxylic acid tert-butyl ester is concommitantly removed during theacid hydrolysis step, necessitating a standard reprotection withdi-tert-butyl dicarbonate, giving key intermediates (V) such as(4-carbamoyl-4-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester. It isnoteworthy that during the cyanohydrin formation there is little or nostereoselectivity with regard to relative stereochemistry, and the(4-carbamoyl-4-hydroxy-cyclohexyl)-carbamic acid tert-butyl esterproduced in this process is a mixture of cis and trans stereoisomers.These isomers can be separated by careful chromatography.

The same 1-keto-derivative could undergo a Wittig reaction withPh₃PCH═CO₂Me to give the α,β-unsaturated carboxylic esterMeO₂C—CH═C<Ring, which could be epoxidised (eg meta-chloroperbenzoicacid) to give the α,β-epoxy-ester. Alternatively this could be formeddirectly from the keto-derivative via a glycidic ester condensation withan α-halogeno-ester. Base hydrolysis would afford theα,β-epoxy-carboxylic acid, which on reduction (eg lithiumtriethylborohydride—see J. Miklefield et al J. Amer. Chem. Soc. 117,1153-1154 (1995) or hydrogenation over platinum oxide (see ArtainonowZh.Obshch.Khim. 28 1355-1359 (1958)) would afford the β-hydroxy acid(Compound (V) Y═CO₂H, n=1, R^(3′)═OH). Alternatively a Reformatskyreaction with the keto-derivative and an α-bromocarboxylic acid esterand zinc, followed by acid hydrolysis would afford theβ-hydroxycarboxylic acid directly. The 1-keto-derivative could alsoundergo a Strecker type synthesis via a Bucherer-Bergs procedure(potassium cyanide/ammonium carbonate) [see T. Scott Yokum et al.Tetrahedron Letters, 38, 4013-4016 (1997)] to give theα-amino-carboxylic acid (Compound (V) Y═CO₂H, n=0, R^(3′)═NH₂).

An alternative route to 1-substituted compounds (V) involves a DielsAlder reaction between butyl acrylate and acetoxy butadiene to give (1).Elimination of acetic acid and hetero Diels Alder reaction with anin-situ generated acyl nitroso compound gives the bicyclic hydroxylamineproduct (3). The ester is transformed to an amide in two steps, andcatalytic hydrogenation is used to reduce the double bond, remove thenitrogen protection and cleave the NO bond. After reprotection of theamino group, the cyclohexane amide with the required stereochemistry isobtained.

Two steps can be avoided by starting with acrylamide:

Compounds of formula (V) substituted by R³ at the 2- or 3-position maybe prepared from the corresponding substituted phenyl derivative1-Y(CH₂)_(n)Ph(—R3)-4-NR₂ (eg where Y=carboxylic acid) by hydrogenationat elevated temperature and pressure using a Pt or Ru catalyst.

Compounds of formula (V) with a 3-hydroxyl group may be prepared from a3,4 oxirane-cyclohexane carboxylic acid by reaction with an amine NHR²R⁴or azide (followed by conversion of the azide to amino). [See forexample K. Krajewski et al. Tetrahedron Asymmetry 10, 4591-4598 (1999)].The ester group maybe epimerised by heating in strong base, hydrolysedto the carboxylic acid and cyclised to the lactone using a conventionalcoupling reagent (EDC). Other conventional reagents eg DCC, Im₂CO, HATUetc. may also be used. The lactone is readily purified bychromatography. The lactone is readily opened with aqueous ammonia intetrahydrofuran to give the required (racemic) amide.

An improved procedure starting from 3-cyclohexene carboxylic acid may beused to prepare single enantiomers. 3-Cyclohexene carboxylic acid (2) isresolved via α-Me benzylamine salt (Schwartz et al, J. Am. Chem. Soc.,100, 5199, (1978)). A higher yield of lactone (3) can be achieved usinga larger excess of reagents. Lactone opening with ammonia gives (4),which is treated with azide to give (5) which has the required transrelative stereochemistry between the amide and N-substituent. Finally,azide reduction and Boc protection gives (1) a compound of formula (V).

R⁴-halides and R⁴-W derivatives, acyl derivatives or aldehydes arecommercially available or are prepared conventionally. The aldehydes maybe prepared by partial reduction of the corresponding ester with lithiumaluminium hydride or di-isobutylaluminium hydride or more preferably byreduction to the alcohol, with lithium aluminium hydride or sodiumborohydride (see Reductions by the Alumino- and Borohydrides in OrganicSynthesis, 2nd ed., Wiley, N.Y., 1997; JOC, 3197, 1984; Org. Synth.Coll., 102, 1990; 136, 1998; JOC, 4260, 1990; TL, 995, 1988; JOC, 1721,1999; Liebigs Ann./Recl., 2385, 1997; JOC, 5486, 1987), followed byoxidation to the aldehyde with manganese (II) dioxide, or by a ‘Swem’procedure (oxalyl chloride/DMSO), or by using potassium dichromate(PDC). The aldehydes may also be prepared from carboxylic acids in twostages by conversion to a mixed anhydride for example by reaction withisobutyl chloroformate followed by reduction with sodium borohydride (R.J. Alabaster et al., Synthesis, 598, 1989) to give the hydroxymethylsubstituted heteroaromatic or aromatic and then oxidation with astandard oxidising agent such as pyridinium dichromate or manganese (II)dioxide. Acyl derivatives may be prepared by activation of thecorresponding ester. R⁴-halides such as bromides may be prepared fromthe alcohol R⁴OH by reaction with phosphorus tribromide indichloromethane/triethylamine. Where X^(2a) is CO and X^(3a) is NR^(13a)the R⁴-halide may be prepared by coupling an X^(4a)NH₂ amine andbromoacetyl bromide. R⁴W derivatives such as methanesulphonylderivatives may be prepared from the alcohol R⁴OH by reaction withmethane sulphonyl chloride. The leaving group W may be converted toanother leaving group W, e.g. a halogen group, by conventional methods.Alternatively the aldehyde R⁵ ₂CHO and sulphonic acid derivative R⁵₂SO₂W may be generated by treatment of the R⁵ ₂H heterocycle withsuitable reagents. For example benzoxazinones, or more preferably theirN-methylated derivatives can be formylated with hexamine in eithertrifluoroacetic acid or methanesulfonic acid, in a modified Duffprocedure [O. I. Petrov et al. Collect. Czech. Chem. Commun. 62, 494-497(1997)]. 4-Methyl-4H-benzo[1,4]oxazin-3-one may also be formylated usingdichloromethyl methyl ether and aluminium chloride giving exclusivelythe 6-formyl derivative.

Reaction of a R⁵ ₂H heterocycle with chlorosulphonic acid gives thesulphonic acid derivative (by methods analogous to Techer et. al., C. R.Hebd. Seances Acad. Sci. Ser.C; 270, 1601, 1970).

The aldehyde R⁵ ₂CHO may be generated by conversion of an R⁵ ₂ halogenor R⁵ ₂ trifluoromethane sulphonyloxy derivative into an olefin withsubsequent oxidative cleavage by standard methods. For example, reactionof a bromo derivative under palladium catalysis withtrans-2-phenylboronic acid under palladium catalysis affords a styrenederivative which upon ozonolysis affords the required R⁵ ₂CHO(Stephenson, G. R., Adv. Asymmetric Synth. (1996), 275-298. Publisher:Chapman & Hall, London).

Where R⁵ ₂ is an optionally substituted benzoimidazol-2-yl group, thecompound of formula (V) where R^(4′) is R⁴ may be obtained by convertinga R^(4′) cyanomethyl group with partial hydrolysis to give the2-ethoxycarbonimidoylethyl group which can then be condensed with anappropriately substituted 1,2-diaminobenzene to give the requiredbenzoimidazol-2-yl group.

R⁵ ₂H heterocycles are commercially available or may be prepared byconventional methods. For example where a benzoxazinone is required, anitrophenol may be alkylated with for example ethyl bromoacetate and theresulting nitro ester reduced with Fe in acetic acid (alternativelyZn/AcOH/HCl or H₂/Pd/C or H₂/Raney Ni). The resulting amine may undergospontaneous cyclisation to the required benzoxazinone, or cyclisationmay be induced by heating in acetic acid. Alternatively a nitrophenolmay be reduced to the aminophenol, which is reacted with chloroacetylchloride [method of X. Huang and C. Chan, Synthesis 851 (1994)] or ethylbromoacetate in DMSO [method of Z. Moussavi et al. Eur. J. Med. Chem.Ther. 24, 55-60 (1989)]. The same general routes can be applied toprepare benzothiazinones [See for example F. Eiden and F. Meinel, Arch.Pharm. 312, 302-312 (1979), H. Fenner and R Grauert Liebigs. Ann. Chem.193-313 (1978)]]. A variety of routes are available to prepare azaanalogues of benzothiazinones via the key corresponding aldehydes. Forinstance, 2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]thiazine-7-carbaldehydemaybe accessed from 5-fluoro-2-picoline (E. J. Blanz, F. A. French, J.R. DoAmaral and D. A. French, J. Med. Chem. 1970, 13,1124-1130) byconstructing the thiazinone ring onto the pyridyl ring thenfunctionalising the methyl substituent, as described in the Examples.The dioxin analogue of this aza substitution pattern,2,3-dihydro-[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde is accessiblefrom Kojic acid by aminolysis from pyrone to pyridone then annelatingthe dioxin ring, again as described in the subsequent experimental data.Other aza substitution patterns with pyridothiazin-3-one,pyridooxazin-3-one, and pyridodioxin ring systems are also accessible,again as described in the Examples. Ortho-aminothiophenols may beconveniently prepared and reacted as their zinc complexes [see forexample V. Taneja et al Chem. Ind. 187 (1984)]. Benzoxazolones may beprepared from the corresponding aminophenol by reaction with carbonyldiimidazole, phosgene or triphosgene. Reaction of benzoxazolones withdiphosporus pentasulfide affords the corresponding 2-thione. Thiazinesand oxazines can be prepared by reduction of the correspondingthiazinone or oxazinone with a reducing agent such as lithium aluminiumhydride.

The amines R^(2′)R^(4′)NH are available commercially or preparedconventionally. For example amines may be prepared from a bromoderivative by reaction with sodium azide in dimethylformamide (DMF),followed by hydrogenation of the azidomethyl derivative overpalladium-carbon. An alternative method is to use potassiumphthalimide/DMF to give the phthalimidomethyl derivative, followed byreaction with hydrazine in DCM to liberate the primary amine.

Amines where X^(2a) is CO and X^(3a) is NR^(13a) may be prepared byreacting an N-protected glycine derivative HO₂C—X^(1a)—NH₂ withX^(4a)—NH₂ by conventional coupling using eg EDC.

Conversions of R^(1a′), R^(1′), R^(2′), R^(3′) and R^(4′) may be carriedout on the intermediates of formulae (IV) and (V) prior to theirreaction to produce compounds of formula (I) in the same way asdescribed above for conversions after their reaction.

The pharmaceutical compositions of the invention include those in a formadapted for oral, topical or parenteral use and may be used for thetreatment of bacterial infection in mammals including humans.

The antibiotic compounds according to the invention may be formulatedfor administration in any convenient way for use in human or veterinarymedicine, by analogy with other antibiotics.

The composition may be formulated for administration by any route, suchas oral, topical or parenteral. The compositions may be in the form oftablets, capsules, powders, granules, lozenges, creams or liquidpreparations, such as oral or sterile parenteral solutions orsuspensions.

The topical formulations of the present invention may be presented as,for instance, ointments, creams or lotions, eye ointments and eye or eardrops, impregnated dressings and aerosols, and may contain appropriateconventional additives such as preservatives, solvents to assist drugpenetration and emollients in ointments and creams.

The formulations may also contain compatible conventional carriers, suchas cream or ointment bases and ethanol or oleyl alcohol for lotions.Such carriers may be present as from about 1% up to about 98% of theformulation. More usually they will form up to about 80% of theformulation.

Tablets and capsules for oral administration may be in unit dosepresentation form, and may contain conventional excipients such asbinding agents, for example syrup, acacia, gelatin, sorbitol,tragacanth, or polyvinylpyrollidone; fillers, for example lactose,sugar, maize-starch, calcium phosphate, sorbitol or glycine; tablettinglubricants, for example magnesium stearate, talc, polyethylene glycol orsilica; disintegrants, for example potato starch; or acceptable wettingagents such as sodium lauryl sulphate. The tablets may be coatedaccording to methods well known in normal pharmaceutical practice. Oralliquid preparations may be in the form of, for example, aqueous or oilysuspensions, solutions, emulsions, syrups or elixirs, or may bepresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives, such as suspending agents, for example sorbitol,methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose,carboxymethyl cellulose, aluminium stearate gel or hydrogenated ediblefats, emulsifying agents, for example lecithin, sorbitan monooleate, oracacia; non-aqueous vehicles (which may include edible oils), forexample almond oil, oily esters such as glycerine, propylene glycol, orethyl alcohol; preservatives, for example methyl or propylp-hydroxybenzoate or sorbic acid, and, if desired, conventionalflavouring or colouring agents.

Suppositories will contain conventional suppository bases, e.g.cocoa-butter or other glyceride.

For parenteral administration, fluid unit dosage forms are preparedutilizing the compound and a sterile vehicle, water being preferred. Thecompound, depending on the vehicle and concentration used, can be eithersuspended or dissolved in the vehicle. In preparing solutions thecompound can be dissolved in water for injection and filter sterilisedbefore filling into a suitable vial or ampoule and sealing.

Advantageously, agents such as a local anaesthetic, preservative andbuffering agents can be dissolved in the vehicle. To enhance thestability, the composition can be frozen after filling into the vial andthe water removed under vacuum. The dry lyophilized powder is thensealed in the vial and an accompanying vial of water for injection maybe supplied to reconstitute the liquid prior to use. Parenteralsuspensions are prepared in substantially the same manner except thatthe compound is suspended in the vehicle instead of being dissolved andsterilization cannot be accomplished by filtration. The compound can besterilised by exposure to ethylene oxide before suspending in thesterile vehicle. Advantageously, a surfactant or wetting agent isincluded in the composition to facilitate uniform distribution of thecompound.

The compositions may contain from 0.1% by weight, preferably from 10-60%by weight, of the active material, depending on the method ofadministration. Where the compositions comprise dosage units, each unitwill preferably contain from 50-500 mg of the active ingredient. Thedosage as employed for adult human treatment will preferably range from100 to 3000 mg per day, for instance 1500 mg per day depending on theroute and frequency of administration. Such a dosage corresponds to 1.5to 50 mg/kg per day. Suitably the dosage is from 5 to 20 mg/kg per day.

No toxicological effects are indicated when a compound of formula (I) ora pharmaceutically acceptable salt or in vivo hydrolysable ester thereofis administered in the above-mentioned dosage range.

The compound of formula (I) may be the sole therapeutic agent in thecompositions of the invention or a combination with other antibiotics orwith a β-lactamase inhibitor may be employed.

Compounds of formula (I) are active against a wide range of organismsincluding both Gram-negative and Gram-positive organisms.

The following examples illustrate the preparation of certain compoundsof formula (I) and the activity of certain compounds of formula (I)against various bacterial organisms.

EXAMPLES Example 1Trans-4-[(8-Hydroxy-quinolin-2-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide oxalate salt

(a) 4-Hydroxy-6-methoxy-[1,5]-naphthyridine

5-Amino-2-methoxypyridine (55 g, 0.44 mol) in methanol (1000 mL) withmethyl propiolate (40 mL, 0.44 mol) was stirred for 48 hours, thenevaporated and the product purified by chromatography on silica gel(dichloromethane) followed by recrystallisation fromdichloromethane-hexane (44.6 g, 48%).

The unsaturated ester (10.5 g, 0.05 mol) in warm Dowtherm A (50 mL) wasadded over 3 minutes to refluxing Dowtherm A, and after a further 20minutes at reflux the mixture was cooled and poured into diethyl ether.The precipitate was filtered to give a solid (6.26 g, 70%).

(b) 1,1,1-Trifluoro-methanesulfonic acid6-methoxy-[1,5]naphthyridin-4-yl ester

Pyridone (1a) (10 g, 0.057 mol) in dichloromethane (200 mL) containing2,6-lutidine (9.94 mL, 0.086 mol) and 4-dimethylaminopyridine (0.07 g,0.0057 mol) was cooled in ice and treated with trifluoromethanesulfonicanhydride (10.5 mL, 0.063 mol). After stirring for 2.5 hours the mixturewas washed with saturated ammonium chloride solution, dried, evaporatedand purified on silica gel (dichloromethane) to give a solid (13.2 g).

(c) 6-Methoxy-[1,5]naphthyridin-4-ylamine

A solution of triflate (1b) (8.0 g) and propylamine hydrochloride (15.8g) in pyridine (120 mL) was heated at reflux for 4 hours. The solventwas evaporated and the mixture dissolved in 0.05M hydrochloric acid (600mL) and washed with dichloromethane. The mixture was basified with 40%sodium hydroxide and extracted with dichloromethane. The extracts weredried, evaporated and chromatographed on silica gel (2-5% methanol indichloromethane) to give an orange solid (3.6 g, 63%).

δH (CDCl₃, 250 MHz), 8.39 (1H, d,), 8.09 (1H, d,), 7.08 (1H, d,), 6.71(1H, d,), 5.25 (2H, brs), 4.05 (3H, s). MS (+ve ion electrospray) m/z:176 (MH⁺).

(d) [4-(6-Methoxy-[1,5]naphthyridin-4-ylcarbamoyl)-cyclohexyl]-carbamicacid tert-butyl ester

Amine (1c) (2.44 g, 13.94 mmol),4-trans-tert-butoxycarbonylamino-cyclohexanecarboxylic acid (3.39 g,13.94 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′, N′-tetramethyluroniumhexafluorophosphate (5.30 g, 13.94 mmol) were combined as a slurry inN,N′-dimethylformamide (70 mL). To this mixture was added triethylamine(3.88 mL, 27.88 mmol) and the reaction vessel was heated to 60° C. for10 hours. After this period the solvent was removed under vacuum and theresidue partitioned between ethyl acetate (2×200 mL) and brine (50 mL).The organic phases were combined and dried over magnesium sulfate afterwhich they were concentrated in vacuo. The resulting oil was purified bycolumn chromatography on silica gel using a dichloromethane and methanolsolvent gradient. This provided the desired compound as a white solid(3.33 g, 60%).

MS (APCI+) m/z 401 (MH+).

(e) 4-Amino-cyclohexanecarboxylic acid(6-methoxy-[1,5]naphthyridin-4-yl)-amide

Amide (1d) (3.33 g, 8.325 mmol) was dissolved in dichloromethane (200mL). To this solution was added trifluoroacetic acid (50 mL) and theresulting mixture stirred at room temperature for 2 hours. The volatileswere removed under reduced pressure and the residue was treated with 4Mhydrochloric acid in 1,4-dioxan (100 mL). The resulting solid wasfiltered and then stirred over potassium carbonate (4.59 g, 33.3 mmol)in a mixture of chloroform and 15% methanol (2×150 mL). The slurry wasfiltered and the filtrate concentrated under vacuum to provide thedesired compound as an off white solid (1.82 g, 73%).

MS (APCI+) m/z 301 (MH+).

(f) Title Compound

Amide (1d) (796 mg, 1.99 mmol) was dissolved in dichloromethane (5 mL)and cooled to 0° C. Trifluoroacetic acid (5 mL) was added and theresulting solution stirred at room temperature for 20 hours. Thereaction was concentrated under vacuum and the residue re-dissolved inanhydrous dichloromethane (5 mL) and methanol (1 mL). To this solutionwas added activated 3 Å molecular sieves (1 g),8-hydroxy-quinoline-2-carbaldehyde (263 mg, 1.52 mmol) and triethylamine(0.21 mL, 1.52 mmol). The resulting solution was stirred at roomtemperature for 20 hours and then sodium borohydride (116 mg, 3.05 mmol)was added. The resulting slurry was stirred at room temperature for afurther 10 hours. The reaction mixture was quenched by the addition ofwater (2 mL) and the volatiles removed in vacuo. The residue waspartitioned between ethyl acetate (2×100 mL) and brine (20 mL). Theorganic phases were combined and dried over magnesium sulfate. Thevolatiles were again removed under reduced pressure and the resultingoil was subjected to purification on silica gel using a methanol anddichloromethane gradient. This afforded the free base of the desiredcompound as a colourless oil (33 mg, 4%).

δH (CD₃OD, 250 MHz) 8.46 (1H, d), 8.34 (1H, d), 8.07 (1H, d), 8.04 (1H,d), 7.35-7.19 (3H, m), 7.11 (1H, d), 6.97 (1H, dd), 4.09 (2H, s), 4.01(3H, s), 2.61-2.49 (2H, m), 2.14-2.01 (4H, m), 1.45-1.22 (2H, m),1.37-1.22 (2H, m). MS (APCI+) m/z 458 (MH+).

A solution of the oil (33 mg) in dichloromethane (1 mL) was added tooxalic acid (6.5 mg) in diethyl ether (10 mL) to generate the oxalatesalt. The title compound was isolated by centrifugation, washing withdiethyl ether and subsequent drying in vacuo.

Example 2Trans-4-[(Benzo[1,2,5]thiadiazol-5-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide fumarate salt

(a) Benzo[1,2,5]thiadiazol-5-yl-methanol

Benzo[1,2,5]thiadiazole-5-carboxylic acid (2.00 g, 11.11 mmol) wasdissolved in tetrahydrofuran (50 mL) and cooled to 0° C. To this wasadded triethylamine (1.80 mL, 12.87 mmol) followed byisobutylchloroformate (1.62 mL, 12.40 mmol) in a dropwise manner. Theresulting slurry was stirred for a further 30 minutes at 0° C. and thenfiltered into a mixture of sodium borohydride (0.83 g, 21.84 mol) in icewater (20 mL). The resulting mixture was stirred at 0° C. for 30minutes, evaporated to one quarter of its volume and then extracted withdichloromethane (3×50 mL). The organic phases were combined and thendried over sodium sulfate. This was followed by concentration underreduced pressure to provide the desired product as a white solid whichwas used without further purification (1.50 g, 81%).

(b) Methanesulfonic acid benzo[1,2,5]thiadiazol-5-ylmethyl ester

Alcohol (2a) (200 mg, 1.20 mmol), was dissolved in dichloromethane (6mL). This solution was cooled to 0° C. and triethylamine (0.22 mL, 1.57mmol) was added. This was followed by the dropwise addition of methanesulfonylchloride (0.11 mL, 1.45 mmol). The resulting mixture was stirredat room temperature for 2 hours and then partitioned between a 10%aqueous solution of sodium hydrogen carbonate (25 mL) anddichloromethane (2×50 mL). The organic phases were combined and driedover magnesium sulfate. They were then dried under reduced pressure toafford the desired product which was used without further purification(241 mg, 70% w/w).

(c) Title Compound

Amine (1e) (160 mg, 0.533 mmol) was dissolved in N,N′-dimethylformamide(5 mL). To this solution was added potassium carbonate (74 mg, 0.533mmol) and mesylate (2b) (130 mg, 0.533 mmol). The resulting suspensionwas stirred at room temperature for 10 hours. The reaction wasconcentrated under vacuum and the residue partitioned between ethylacetate (2×100 mL) and brine (20 mL). The organic phases were combinedand dried over magnesium sulfate. The volatiles were again removed underreduced pressure and the resulting oil was subjected to purification onsilica gel using a methanol and dichloromethane gradient. This affordedthe free base of the desired compound as a colourless oil (71 mg, 30%).

δH (CDCl₃, 250 MHz), 9.50 (1H, bs), 8.70 (1H, d), 8.54 (1H, d), 8.22(1H, d), 7.97 (2H, m), 7.63 (1H, dd), 7.13 (1H, m), 4.10 (3H, s), 4.00(2H, s), 2.65-2.62 (1H, m), 2.46-2.40 (1H, m), 2.21-2.17 (4H, m),1.71-1.66 (2H, m), 1.38-1.20 (2H, m). MS (APCI+) m/z 449 (MH+).

A solution of the oil (71 mg) in dichloromethane (1 mL) was added tofumaric acid (18 mg) in dichloromethane and methanol (1:1, 10 mL) togenerate the fumarate salt. The title compound was isolated by removalof volatiles in vacuo.

Example 3Trans-4-[(1H-Pyrrolo[2,3-b]pyridin-2-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin4-yl)-amide fumarate salt

(a) 7-Azaindole-2-carboxylic acid.

A solution of 7-azaindole (2.0 g) in tetrahydrofuran (30 ml) was cooledto −70° C. and n-butyllithium (1.6M in hexanes, 11.1 ml) was addeddropwise. After 0.5 h at −70° C., carbon dioxide was bubbled through for10 min, followed by 10 min stirring. The mixture was allowed to warm to0° C. and the mixture was evaporated under vacuum to approximatelyhalf-volume. Fresh tetrahydrofuran (15 ml) was added, the mixture wascooled to −70° C. and tert-butyl lithium (1.7M in pentane, 10.5 ml) wasadded dropwise. After stirring for 1 h at −70° C., carbon dioxide wasbubbled through for 10 min followed by stirring for 30 min. Water (1.2ml) was added and the mixture was allowed to warm to room temperaturebefore pouring into saturated ammonium chloride. The aqueous solutionwas washed with diethyl ether, filtered and acidified to pH3.5. Thewhite precipitate was collected and dried to give the acid (2.38 g).

MS (+ve ion electrospray) m/z 163 (MH+).

(b) Methyl 7-azaindole-2-carboxylate.

Acid (3a) (1.0 g) was partially dissolved in N,N′-dimethylformamide (20ml) and methanol (2 ml) and treated dropwise withtrimethylsilyldiazomethane (2M in hexanes, 3.1 ml). The mixture wasstirred overnight then evaporated. Chromatography on silica using anethyl acetate and hexane solvent gradient gave the ester (0.35 g).

MS (+ve ion electrospray) m/z 177 (MH+).

(c) 7-Azaindole-2-carboxaldehyde.

Ester (3b) (0.34 g) in tetrahydrofuran (5 ml) was treated dropwise withlithium aluminium hydride (1M in tetrahydrofuran, 1.9 ml) at 0° C. After2 h the mixture was treated with 8% sodium hydroxide, dichloromethaneand sodium sulfate, filtered and evaporated. The resulting crude alcoholwas dissolved in tetrahydrofuran (4 ml) and stirred with manganese (II)oxide (0.74 g) for 4 h. Filtration and evaporation of solvent gave thealdehyde (100 mg).

MS (+ve ion electrospray) m/z 147 (MH+).

(d) Title Compound

Amine (1e) (245 mg, 0.822 mmol) and aldehyde (3c) (120 mg, 0.822 mmol)was dissolved in chloroform (6 mL) and methanol (2 mL). The solution washeated to 70° C. for 5 hours with 3 Å molecular sieves (1 g). After thisperiod the mixture was cooled to 0° C. and sodium triacetoxyborohydride(522 mg, 2.466 mmol) was added. The mixture was stirred at roomtemperature for 10 hours and then quenched by the addition of water (2mL). The volatiles were removed, in vacuo and the residue partitionedbetween ethyl acetate (2×100 mL) and brine (25 mL). The organic phaseswere combined and dried over magnesium sulfate then evaporated. Theresulting oil was purified by silica gel chromatography using adichloromethane and methanol solvent gradient. This provided the freebase of the desired compound as a colourless oil (74 mg, 22%).

δH (CDCl₃, 250 MHz), 9.51 (1H, bs), 8.68 (1H, d), 8.50 (1H, d), 8.28(1H, d), 8.22 (1H, d), 7.84 (1H, dd), 7.15 (1H, d), 7.05 (1H, dd), 6.31(1H, s), 4.11 (2H, s), 4.09 (3H, s), 2.64-2.60 (1H, m), 2.42-2.37 (1H,m), 2.19-2.17 (4H, m), 1.73-1.63 (2H, m), 1.31-1.22 (2H, m).

MS (APCI+) m/z 431 (MH+).

The fumarate salt was prepared by the method of Example 2.

Example 4Trans-4-[(3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-ylmethyl)-amino]-cyclohexanecarboxylic acid (6-methoxy-[1,5]naphthyridin-4-yl)-amide fumarate salt

a) 3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid

3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid methyl ester(6.74 g) was suspended in tetrahydrofuran (100 mL) and 2M sodiumhydroxide (30 mL) was added followed by water (20 mL). The solution wasstirred for 2.5 hours, evaporated to half volume and acidified with 2Mhydrochloric acid. The product was collected, washed with water anddried in vacuo, to give a white solid (6.2 g).

MS (−ve ion electrospray) m/z 208 (M−H)⁻

(b) 6-Hydroxymethyl-4H-benzo[1,4]thiazin-3-one

Acid (4a) in tetrahydrofuran (50 mL) and triethylamine (4.7 mL) wascooled to 0° C. and isobutylchloroformate (4.02 mL) was added dropwiseand the solution was stirred at 0° C. for 2 hours, when it was filteredinto a stirred solution of sodium borohydride (3.14 g) in ice/water (50mL). The mixture was stirred at 0° C. for 1 hour and allowed to warm toroom temperature. It was acidified with 2M hydrochloric acid, evaporatedto half volume, and the resulting product was collected, washed withwater and dried in vacuo, to give a white solid (4.5 g).

MS (−ve ion electrospray) m/z 194 (M−H)⁻

(c) 3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbaldehyde

A stirred solution of alcohol (4b) (3.5 g) in chloroform (150 mL) andtetrahydrofuran (300 mL) was treated with manganese dioxide (7.8 g) for18 hours and was filtered and evaporated to give a white solid (2.5 g).

MS (−ve ion electrospray) m/z 194 (M−H)⁻

(d) Title Compound

Amine (1e) (260 mg, 0.866 mmol) and aldehyde (4c) (167 mg, 0.866 mmol)was dissolved in chloroform (5 mL) and methanol (3 mL). The solution washeated to 70° C. for 7 hours with 3 Å molecular sieves (1 g). After thisperiod the mixture was cooled to 0° C. and sodium triacetoxyborohydride(550 mg, 2.598 mmol) was added. The mixture was stirred at roomtemperature for 10 hours and then quenched by the addition of water (2mL). The volatiles were removed in vacuo and the residue was purified bysilica gel chromatography using a dichloromethane and methanol solventgradient. This provided the free base of the desired compound as acolourless oil (145 mg, 35%).

δH (d₆-DMSO, 250 MHz), 10.52 (1H, bs), 9.80 (1H, bs), 8.66 (1H, d), 8.39(1H, d), 8.26 (1H, d), 7.31 (1H, d), 7.26 (1H, d), 6.99-6.96 (2H, m),4.14 (3H, s), 3.73 (2H, s), 3.44 (2H, s), 2.68 (1H, m), 2.51-2.48 (1H,m), 2.04-1.90 (4H, m), 1.52-1.47 (2H, m), 1.24-1.17 (2H, m).

MS (+ve ion electrospray) m/z 478(MH+).

The fumarate salt was prepared by the method of Example 2.

Example 5Trans-4-[(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide fumarate salt

(a) (2,3-Dihydro-benzo[1,4]dioxin-6-yl)-methanol

2,3-Dihydro-benzo[1,4]dioxine-6-carbaldehyde [RN 29668-44-8] (3.04 g,18.54 mmol) was dissolved in ethanol (100 mL) and cooled to 0° C. To theresulting solution was added sodium borohydride (1.41 g, 37.07 mmol).The resulting slurry was stirred at room temperature for 1 hour and thenquenched with water (10 mL) before being concentrated to dryness underreduced pressure. The residue was partitioned between a 5% aqueoussolution of sodium hydrogen carbonate (20 mL) and dichloromethane (2×50mL). The organic phases were combined and dried over magnesium sulfatethen evaporated under reduced pressure to provide and oil which waspurified on silica gel using a dichloromethane and methanol solventgradient. This provided the desired product as a colourless oil (3.00 g,97%).

(b) Methanesulfonic acid 2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl Ester

Alcohol (5a) (640 mg, 3.855 mmol), was dissolved in dichloromethane (20mL). This solution was cooled to 0° C. and triethylamine (0.70 mL, 5.012mmol) was added. This was followed by the dropwise addition of methanesulfonylchloride (0.36 mL, 4.627 mmol). The resulting mixture wasstirred at room temperature for 2 hours and then partitioned between a10% aqueous solution of sodium hydrogen carbonate (25 mL) anddichloromethane (2×100 mL). The organic phases were combined and driedover magnesium sulfate. They were then dried under reduced pressure toafford the desired product which was used without further purification(1.00 g, 60% w/w).

(c) Title Compound

Amine (1e) (150 mg, 0.50 mmol) was dissolved in N,N′-dimethylformamide(10 mL). To this solution was added potassium carbonate (76 mg, 0.55mmol) and mesylate (5b) (122 mg, 0.50 mmol). The resulting suspensionwas stirred at 50° C. for 3 hours. The reaction was concentrated undervacuum and the residue partitioned between dichloromethane (2×100 mL)and an aqueous solution of saturated sodium hydrogen carbonate (20 mL).The organic phases were combined and dried over magnesium sulfate. Thevolatiles were again removed under reduced pressure and the resultingoil was subjected to purification on silica gel using a methanol andethyl acetate gradient. This afforded the free base of the desiredcompound as a colourless oil (70 mg, 31%).

δH (CDCl₃, 250 MHZ), 9.48 (1H, bs), 8.68 (1H, d), 8.52 (1H, d), 8.21(1H, d), 7.15 (1H, d), 6.86-6.79 (3H, m), 4.24 (4H, m), 4.14 (3H, s),3.79 (2H, m), 2.88-2.61 (1H, m), 2.49-2.40 (1H, m), 2.20-2.15 (4H, m),1.68-1.63 (2H, m), 1.58-1.34 (2H, m). MS (APCI+) m/z 449 (MH+).

The fumarate salt was prepared by the method of Example 2.

Example 6Trans-4-[(Benzo[1,2,3]thiadiazol-5-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide fumarate salt

(a) Benzo[1,2,3]thiadiazol-5-yl-methanol

Benzo[1,2,3]thiadiazole-5-carboxylic acid (2.70 g, 15.0 mmol) wasdissolved in tetrahydrofuran (25 mL) and cooled to 0° C. To this wasadded triethylamine (2.50 mL, 18.0 mmol) followed byisobutylchloroformate (2.15 mL, 16.5 mmol) in a dropwise manner. Theresulting slurry was stirred for a further 30 minutes at 0° C. and thenfiltered into a mixture of sodium borohydride (1.14 g, 30 mmol) in icewater (20 mL). The resulting mixture was stirred at 0° C. for 15minutes, evaporated to one quarter of its volume and then partitionedbetween a saturated aqueous solution of sodium hydrogen carbonate (20mL) and ethyl acetate (3×50 mL). The organic phases were combined andthen dried over sodium sulfate. This was followed by concentration underreduced pressure to provide an oil which was purified by columnchromatography on silica gel using an ethyl acetate and hexane solventsystem. This provided the desired product as a yellow solid (1.40 g,56%).

(b) Methanesulfonic acid Benzo[1,2,3]thiadiazol-5-ylmethyl ester

Alcohol (6a) (150 mg, 0.904 mmol) was dissolved in dichloromethane (2mL). This solution was cooled to 0° C. and triethylamine (0.14 mL, 0.994mmol) was added. This was followed by the dropwise addition of methanesulfonylchloride (0.07 mL, 0.904 mmol). The resulting mixture wasstirred at room temperature for 1 hour and then partitioned betweenwater (25 mL) and dichloromethane (2×50 mL). The organic phases werecombined and dried over magnesium sulfate. They were then dried underreduced pressure to afford the desired product which was used withoutfurther purification.

(c) Title Compound

Amine (1e) (50 mg, 0.166 m mol) was dissolved in N,N′-dimethylformamide(3 mL). To this solution was added potassium carbonate (46 mg, 0.332mmol) and mesylate (6b) (218 mg, 0.893 mmol). The resulting suspensionwas stirred at room temperature for 10 hours. The reaction wasconcentrated under vacuum and the residue partitioned between ethylacetate (2×100 mL) and brine (20 mL). The organic phases were combinedand dried over magnesium sulfate. The volatiles were again removed underreduced pressure and the resulting oil was subjected to purification onsilica gel using a methanol and dichloromethane gradient. This affordedthe free base of the desired compound as a colourless oil (22 mg, 29%).

δH (CDCl₃, 250 MHz), 9.51 (1H, bs), 8.69 (1H, d), 8.61 (1H, m), 8.51(1H, d), 8.21 (1H, d), 8.03 (1H, d), 7.72 (1H, dd), 7.16 (1H, d), 4.11(3H, s), 4.00 (2H, s), 2.70-2.64 (1H, m), 2.47-2.41 (1H, m), 2.23-2.18(4H, m), 1.76-1.63 (2×, m), 1.40-1.25 (211, m).

MS (APCI+) m/z 449 (MH+).

The fumarate salt was prepared by the method of Example 2.

Example 7Trans-4-[(3-Methyl-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide oxalate salt

(a) 3-Methyl-2-oxo-2,3-dihydro-benzooxazole-6-carbaldehyde

3-Methyl-3H-benzooxazol-2-one (2.00 g, 13.42 mmol) andhexamethylenetetramine (3.76 g, 26.84 mmol) were dissolved intrifluoroacetic acid (20 mL) and heated at reflux for 20 hours. Thevolatiles were removed in vacuo and the residue was treated with icewater (60 mL). The resultant mixture was stirred for 30 minutes and thenmade basic with sodium carbonate. The solid was isolated by filtrationand washed with water then dried under vacuum. The solid was purified bycolumn chromatography on silica gel eluting with an ethyl acetate andhexane solvent gradient. This provided the desired product as a whitesolid (1.07 g, 45%).

δH (CDCl₃, 250 MHz), 9.95 (1H, s), 7.80-7.76 (1H, dd), 7.33 (1H, d),7.10 (1H, d), 3.48 (3H, s).

(b) Title Compound

Amide (1d) (311 mg, 0.778 mmol) was dissolved in dichloromethane (2 mL)and cooled to 0° C. Trifluoroacetic acid (2 mL) was added and theresulting solution stirred at room temperature for 1 hour. The reactionwas concentrated under vacuum and the residue re-dissolved in anhydrousdichloromethane (5 mL) and methanol (1 mL). To this solution was addedactivated 4 Å molecular sieves (1 g), aldehyde (7a) (138 mg, 0.778 mmol)and diisopropyl ethylamine (0.40 mL, 2.333 mmol). The resulting solutionwas stirred at room temperature for 5 hours and them sodium borohydride(89 mg, 2.333 mmol) was added. The resulting slurry was stirred at roomtemperature for a further 48 hours. The reaction mixture was quenched bythe addition of water (2 mL) and the volatiles removed in vacuo. Theresidue was partitioned between ethyl acetate (2×100 mL) and brine (20mL). The organic phases were combined and dried over magnesium sulfate.The volatiles were again removed under reduced pressure and theresulting oil was subjected to purification on silica gel using amethanol and dichloromethane gradient. This afforded the free base ofthe desired compound as a colourless oil (50 mg, 14%).

δH (CD₃OD, 250 MHz), 8.66 (1H, d), 8.54 (1H, d), 8.25 (1H, d), 7.40 (1H,m), 7.34-7.24 (2H, m), 7.21 (1H, d), 4.22 (3H, s), 4.03 (2H, s), 3.46(3H, s), 2.80-2.65 (2H, m), 2.24 (4H, m), 1.58-1.53 (2H, m), 1.41-1.33(2H, m).

MS (APCI+) m/z 462 (MH⁺).

The oxalate salt was prepared by the method of Example 1.

Example 8Trans-4-[(3-Oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide fumarate salt

(a) (4-Formyl-2-nitro-phenoxy)-acetic acid ethyl ester

A solution of 4-hydroxy-3-nitro-benzaldehyde (6.9 g) and ethylbromoacetate (5.0 mL) in dimethylformamide (250 mL) was treated withanhydrous potassium carbonate (10 g) and the mixture was heated at 60°C. for 18 hours and evaporated to dryness. The residue was partitionedbetween water and diethyl ether, and the diethyl ether layer was washedwith 0.5M sodium hydroxide. It was then dried over anhydrous sodiumsulfate and evaporated to give an oil that was chromatographed on silicagel (ethyl acetate/dichloromethane) to afford an oil (1.9 g).

MS (+ve ion electrospray) m/z 253 (MH+).

(b) 3-Oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxaldehyde

Ester (8a) (1.9 g) in acetic acid (40 mL) was treated with iron powder(4.2 g) and the mixture was stirred at 60° C. for 0.75 hours, filteredand evaporated to dryness. It was partitioned between aqueous sodiumbicarbonate and ethyl acetate. The organic fraction was chromatographedon silica gel (ethyl acetate) to give a white solid (0.88 g).

MS (−ve ion electrospray) m/z 176 (M−H)−

(c) Title Compound

Amine (1e) (200 mg, 0.66 mmol) and aldehyde (8b) (130 mg, 0.73 mmol) wasdissolved in chloroform (5 mL) and methanol (3 mL). The solution washeated to reflux for 5 hours with 3 Å molecular sieves (1g). Thesolvents were then removed by evaporation and replaced withN,N′-dimethylformamide (2 mL) and toluene (2 mL) The mixture was stirredat reflux for a further 1 hour. These solvents were removed in vacuo andreplaced with chloroform (2 mL) and methanol (2 mL). The mixture wascooled to 0° C. and sodium borohydride (230 mg, 6.05 mmol) was added.The mixture was then stirred at room temperature for 1 hour and quenchedby the addition of water (2 mL). The volatiles were removed in vacuo andthe residue was partitioned between chloroform (2×100 mL) and asaturated aqueous solution of sodium hydrogen carbonate (20 mL). Theorganic phases were combined, dried over magnesium sulfate and thenconcentrated under vacuum. The resulting oil was purified by silica gelchromatography using an ethyl acetate and methanol solvent gradient.This provided the desired compound as a colourless solid.Recrystallisation from ethyl acetate and methanol afforded the free baseof the desired compound (60 mg, 19%).

δH (CD₃OD, 250 MHz), 8.62 (1H, d), 8.51 (1H, d), 8.20 (1H, d), 7.27 (1H,d), 7.03-6.93 (3H, m), 4.56 (2H, s), 4.10 (3H, s), 3.86 (2H, s),2.75-2.60 (2H, m), 2.20-2.16 (4H, m), 1.67-1.63 (2H, m), 1.42-1.28 (2H,m).

The fumarate salt was prepared by the method of Example 2.

Example 9Trans-4-[(7-Fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl-amide Dioxalate Salt

(a) 5-Amino-2-fluoro-4-hydroxy-benzonitrile

This was prepared from 2-fluoro-4-hydroxy-benzonitrile by nitration(concentrated nitric acid in acetic acid at 40° C.) followed byhydrogenation in ethanol over 10% palladium/carbon.

(b) 7-Fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonitrile

This was prepared by the general method of Xian Huang and Cheng-ChuChan, Synthesis, 851 (1984). A mixture of nitrile (9a) (1 g),benzyltriethylammonium chloride (1.5 g) and sodium bicarbonate (2.22 g)in chloroform (20 ml) at 0° C. was treated with chloroacetyl chloride(0.632 mL) in chloroform (5 mL) and then stirred at 5° C. for 1 hour andthen heated at 55° C. for 5 hours. The mixture was evaporated todryness, treated with water, and filtered to give a solid that wasrecrystallised from ethanol to give a white solid (0.35 g). A further(0.24 g) was obtained after chromatography of the mother liquors onsilica gel (chloroform then methanol/dichloromethane).

MS (−ve ion. electrospray) m/z 191 (M−H)⁻

(c) 7-Fluoro-3-oxo-3,4-Dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid

Nitrile (9b) (0.2 g) was heated under reflux in tetrahydrofuran (20 mL)and water (20 mL) containing sodium hydroxide (0.167 g) for 72 hours. Itwas acidified with 2M hydrochloric acid and the product was collectedand dried in vacuo to give a white solid (0.18 g).

MS (−ve ion electrospray) m/z 210 (M−H)⁻

(d) 7-Fluoro-6-hydroxymethyl-4H-benzo[1,4]oxazin-3-one

This was prepared from acid (9c) (1.7 g) via reduction of the mixedanhydride in a manner analogous to Example 4 to give a solid (0.7 g).

MS (−ve ion electrospray) m/z 196 (M−H)⁻

(e) 7-Fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxaldehyde

This was prepared from alcohol (9d) (0.7 g) by oxidation with manganesedioxide according to the procedure in Example 4 to give a solid (0.51g).

MS (−ve ion electrospray) m/z 194 (M−H)⁻

(f) Title Compound

Amine (1e) (300 mg, 1.00 mmol) and aldehyde (9e) (214 mg, 1.10 mmol)were dissolved in chloroform (5 mL) and methanol (3 mL). The solutionwas heated to reflux for 4 hours with 3 Å molecular sieves (1 g). Afterthis period the mixture was cooled to 0° C. and sodium borohydride (230mg, 6.05 mmol) was added. The mixture was stirred at room temperaturefor 10 hours and then quenched by the addition of water (2 mL). Thevolatiles were removed in vacuo and the residue was partitioned betweenchloroform (2×100 mL) and a saturated aqueous solution of sodiumhydrogen carbonate (20 mL). The organic phases were combined, dried overmagnesium sulfate and then concentrated under vacuum. The resulting oilwas purified by silica gel chromatography using an ethyl acetate andmethanol solvent gradient. This provided the free base of the desiredcompound as a colourless oil (43 mg, 9%).

δH (CDCl₃, 250 MHz), 9.51 (1H, bs), 8.68 (1H, d), 8.51 (1H, d), 8.22(1H, d), 7.16 (1H, d), 6.87 (1H, d), 6.70 (1H, d), 4.56 (2H, s), 4.10(3H, s), 3.78 (2H, s), 2.60-2.40 (2H, m), 2.16-2.05 (4H, m), 1.76-1.66(2H, m), 1.39-1.25 (2H, m).

MS (APCI+) m/z 480 (MH+).

The oxalate salt was prepared by the method of Example 1.

Example 10Trans-4-[(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-cyclohexanecarboxylicacid (8-fluoro-6-methoxy-quinolin-4-yl)-amide Fumarate Salt

(a) 8-Fluoro-6-methoxy-quinolin-4-ol

2-Fluoro-4-methoxy-phenylamine (3.80 g, 26.7 mmol) and methyl propiolate(2.37 ml, 0.267 mol) in methanol (100 ml) was stirred for 72 hours atroom temperature, then heated at 50° C. for 24 hours. It was evaporatedand the product purified by chromatography on silica gel(dichloromethane) to give a solid (1.66 g), a portion of which wasrecrystallised from dichloromethane-hexane.

The unsaturated ester (0.96 g) in warm Dowtherm A (5 ml) was added over3 minutes to refluxing Dowtherm A (5 ml), and after a further 20 minutesat reflux the mixture was cooled and poured into diethyl ether. Theprecipate was filtered to give the title compound (0.50 g, 61%)

(b) 1,1,1-Trifluoro-methanesulfonic acid8-fluoro-6-methoxy-quinolin-4-yl ester

Pyridone (10a) (0.48 g) and dimethylaminopyridine (0.03 g) indichloromethane (20 ml) and 2,6-lutidine (0.48 ml) was treated dropwisewith triflic anhydride (0.48 ml) and the mixture was stirred at roomtemperature for 4 hours. It was washed with saturated ammonium chloride,dried, evaporated, and chromatographed on silica gel (dichloromethane)to afford a yellow solid (0.69 g).

MS (+ve ion electrospray) m/z 326 (MH+).

(c) 8-Fluoro-6-methoxy-quinolin-4-ylamine

A solution of triflate (10b) (0.69 g) in pyridine (10 ml) was treatedwith n-propylamine hydrochloride (1.2 g) and the mixture heated atreflux for 16 hours. The reaction mixture was evaporated, dissolved in0.05M HCl, washed with dichloromethane, basified with sodium hydroxidesolution and re-extracted with dichloromethane. The combined organicphases were dried over sodium sulfate, evaporated, and chromatographedon silica gel (2-5% methanol in dichloromethane) to afford an orangesolid (1.0 g).

MS (+ve ion electrospray) m/z 193 (MH⁺).

(d) [4-(8-Fluoro-6-methoxy-quinolin-4-ylcarbamoyl)-cyclohexyl]-carbamicacid tert-butyl ester

Amine (10c) (1.333 g, 6.943 mmol),4-trans-tert-butoxycarbonylamino-cyclohexanecarboxylic acid (1.68 g,6.943 mmol) and O-(7-azabenzotriazol-1-yl)—N,N,N′N′-tetramethyluroniumhexafluorophosphate (2.64 g, 6.943 mmol) were combined as a slurry inN,N′-dimethylformamide (70 mL). To this mixture was added triethylamine(1.93 mL, 13.87 mmol) and the reaction vessel was heated to 60° C. for10 hours. After this period the solvent was removed under vacuum and theresidue partitioned between ethyl acetate (2×200 mL) and brine (50 mL).The organic phases were combined and dried over magnesium sulfate afterwhich they were concentrated in vacuo. The resulting oil was purified bycolumn chromatography on silica gel using a dichloromethane and methanolsolvent gradient. This provided the desired compound as an off whitesolid (1.67 g, 58%).

MS (APCI+) m/z 418 (MH+).

(e) 4-Amino-cyclohexanecarboxylic Acid(8-fluoro-6-methoxy-quinolin-4-yl)-amide

Amide (10d) (1.47 g, 3.525 mmol) was dissolved in dichloromethane (20mL). To this solution was added trifluoroacetic acid (10 mL) and theresulting mixture stirred at room temperature for 3 hours. The volatileswere removed under reduced pressure and the residue was treated with 4Mhydrochloric acid in 1,4-dioxan (50 mL). The resulting solid wasfiltered and then stirred over potassium carbonate (1.95 g, 14.1 mmol)in a mixture of chloroform and 15% methanol (2×100 mL). The slurry wasfiltered and the filtrate concentrated under vacuum to provide thedesired compound as an off white solid (0.615 g, 55%).

MS (APCI+) m/z 318 (MH+).

(f) Title Compound

4-Amino-cyclohexanecarboxylic acid(8-fluoro-6-methoxy-quinolin-4-yl)-amide (10e) (186 mg, 0.587 mmol) wasdissolved in N,N′-dimethylformamide (5 mL). To this solution was addedpotassium carbonate (130 mg, 0.939 mmol) methanesulfonic acid2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl ester (5b) (215 mg, 0.881 mmol).The resulting suspension was stirred at room temperature for 10 hours.The reaction was concentrated under vacuum and the residue partitionedbetween ethyl acetate (2×100 mL) and brine (20 mL). The organic phaseswere combined and dried over magnesium sulfate. The volatiles were againremoved under reduced pressure and the resulting oil was subjected topurification on silica gel using a methanol and dichloromethanegradient. This afforded the free base of the desired compound as acolourless oil (130 mg, 48%).

δH (CDCl₃, 250 MHz), 8.81 (1H, bs), 8.67 (1H, d), 8.16 (1H, d), 7.12(1H, m), 7.08 (1H, dd), 7.01 (1H, m), 6.88 (1H, m), 6.80 (1H, m), 4.21(4H, m), 3.96 (3H, s), 3.77 (2H, m), 2.68 (1H, m), 2.46 (1H, m),2.12-1.95 (4H, m), 1.58-1.53 (2H, m), 1.32-1.25 (2H, m). MS (APCI+) m/z466 (MH+).

The fumarate salt was prepared by the method of Example 2.

Example 11Trans-4-[(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-quinolin-4-yl)-amide fumarate salt

(a) 4-Amino-6-methoxyquinoline

Curtius rearrangement of 6-methoxyquinoline-4-carboxylic acid (Example51a of WO99/37635)(4 g, 20 mmol) with diphenylphosphoryl azide (4.3 mL,20 mmol) and triethylamine (3.5 mL) in tert-butanol (25 ml) at 85° C.gave, after chromatography (silica gel, ethyl acetate-dichloromethane)the N-tert-butoxycarbamate (2.47 g). Treatment with aqueous hydrochloricacid at reflux, followed by basification and extraction with ethylacetate gave the 4-aminoquinoline (0.74 g).

This compound may also be prepared from 4-hydroxy-6-methoxyquinoline bychlorination with phosphorus oxychloride, to give the 4-chloroquinoline,followed by treatment with n-propylamine hydrochloride.

(b) [4-(6-Methoxy-quinolin-4-ylcarbamoyl)-cyclohexyl]-carbamic acidtert-butyl ester

Amine (11a) (4.31 g, 24.77 mmol),4-trans-tert-butoxycarbonylamino-cyclohexanecarboxylic acid (6.02 g,24.77 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (9.41 g, 24.17 mmol) were combined as a slurry inN,N′-dimethylformamide (100 mL). To this mixture was added triethylamine(6.89 mL, 49.54 mmol) and the reaction vessel was heated to 60° C. for10 hours. After this period the solvent was removed under vacuum and theresidue partitioned between ethyl acetate (2×200 mL) and brine (50 mL).The organic phases were combined and dried over magnesium sulfate afterwhich they were concentrated in vacuo. The resulting oil was purified bycolumn chromatography on silica gel using a dichloromethane and methanolsolvent gradient. This provided the desired compound as a white solid(9.50 g, 96%).

MS (APCI+) m/z 400 (+).

(c) 4-Amino-cyclohexanecarboxylic acid (6-methoxy-quinolin-4-yl)-amide

Amide (11b) (13.0 g, 32.58 mmol) was dissolved in dichloromethane (200mL). To this solution was added trifluoroacetic acid (50 mL) and theresulting mixture stirred at room temperature for 3 hours. The volatileswere removed under reduced pressure and the residue was treated with 4Mhydrochloric acid in 1,4-dioxan (100 mL). The resulting solid wasisolated by filtration and stirred over potassium carbonate (12.66 g,91.75 mmol) in a mixture of chloroform and 15% methanol (2×150 mL). Theslurry was filtered and the filtrate concentrated under vacuum toprovide the desired compound as an off white solid (6.00 g, 62%).

MS (APCI+) m/z 300 (MH+)

(d) Title Compound

Amine (11c) (200 mg, 0.667 mmol) was dissolved in N,N′-dimethylformamide(10 mL). To this solution was added potassium carbonate (276 mg, 2.00mmol) methanesulfonic acid 2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl ester(5b) (488 mg, 2.00 mmol). The resulting suspension was stirred at roomtemperature for 10 hours and then at 60° C. for 2 hours. The reactionwas concentrated under vacuum and the residue partitioned between ethylacetate (2×100 mL) and an aqueous solution of saturated sodium hydrogencarbonate (20 mL). The organic phases were combined and dried overmagnesium sulfate. The volatiles were again removed under reducedpressure and the resulting oil was subjected to purification on silicagel using a methanol and dichloromethane gradient. This afforded thefree base of the desired compound as a colourless oil (87 mg, 48%).

δH (CDCl₃, 250 MHz), 8.68 (1H, d), 8.32 (1H, d), 8.30 (1H, bs), 8.00(1H, d), 7.39 (1H, dd), 7.12 (1H, d), 6.84-6.76 (3H, m), 4.25 (4H, s),3.93 (3H, s), 3.71 (2H, s), 2.58 (1H, m), 2.44 (1H, m), 2.20-2.01 (4H,m), 1.75-1.55 (2H, m), 1.25-1.10 (2H, m). MS (APCI+) m/z 448 (MH+).

The fumarate salt was prepared by the method of Example 2.

Example 12Trans-4-[(Benzo[1,2,5]thiadiazol-5-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-quinolin-4-yl)-amide fumarate salt

Amine (11c) (138 mg, 0.45 mmol) was dissolved in N,N′-dimethylformamide(3 mL). To this solution was added potassium carbonate (169 mg, 0.69mmol) methanesulfonic acid benzo[1,2,5]thiadiazol-5-ylmethyl ester (2b)(169 mg, 0.69 mmol). The resulting suspension was stirred at roomtemperature for 10 hours. The reaction was concentrated under vacuum andthe residue partitioned between ethyl acetate (2×100 mL) and brine (20mL). The organic phases were combined and dried over magnesium sulfate.The volatiles were again removed under reduced pressure and theresulting oil was subjected to purification on silica gel using amethanol and dichloromethane gradient. This afforded the free base ofthe desired compound as a colourless oil (67 mg, 33%).

δH (CDCl₃, 250 MHz), 8.71 (1H, d), 8.16 (1H, d), 8.04 (1H, d), 7.95 (2H,m), 7.67-7.60 (2H, m), 7.22 (1H, dd), 7.00 (1H, d), 4.05 (2H, s), 3.98(3H, s), 2.65 (1H, m), 2.44 (1H, m), 2.17 (4H, m), 1.75-1.71 (2H, m),1.33-1.25 (2H, m). MS (+ve ion electrospray) m/z 448 (MH+).

The fumarate salt was prepared by the method of Example 2.

Example 13Trans-4-[(2-Oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazin-7-ylmethyl)-amino]-cyclohexanecarboxylicAcid (6-methoxy-[1,5]naphthyridin-4-yl)-amide oxalate salt

(a) 6-Methoxycarbonylmethylsulfanyl-5-nitro-nicotinic acid methyl ester

A solution of 6-chloro-5-nitro-nicotinic acid methyl ester (1.0 g)[prepared as described by A. H. Berrie et al. J. Chem. Soc. 2590-2594(1951)] in dichloromethane (10 mL) containing triethylamine (0.76 mL)was treated with mercapto-acetic acid methyl ester (0.44 mL) and thesolution was stirred at room temperature for 1 hour and evaporated todryness. Sodium bicarbonate solution was added and the mixture wasextracted with dichloromethane, dried (anhydrous sodium sulfate) andevaporated to afford a solid (1.0 g).

MS (+ve ion electrospray) m/z 287 (MH+).

(b) 2-Oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine-7-carboxylic acidmethyl ester

The ester (13a) (1.0 g) in acetic acid (50 mL) was treated with ironpowder (10 g) and the mixture was stirred and heated at 60° C. for 1hour, cooled and filtered. The filtrate was evaporated, treated withsodium bicarbonate solution and extracted with warm chloroform. It wasdried (anhydrous sodium sulfate) and evaporated to give a white solid(0.85 g).

MS (+ve ion electrospray) m/z 225 (MH+).

(c) 2-Oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine-7-carboxylic acid

The ester (13b) (2.8 g) was hydrolysed with aqueous sodium hydroxide intetrahydrofaran by the method of Example (4a) to afford a solid (2.5 g).

MS (−ve ion electrospray) m/z 209 (M−H⁻).

(d) 7-Hydroxymethyl-1H-pyrido[2,3-b][1,4]thiazin-2-one

The carboxylic acid (13c) (2.48 g) was reacted withisobutylchloroformate and sodium borohydride by the method of Example(4b) to afford a solid (1.3 g), after recrystallisation fromchloroform-methanol (9:1).

MS (+ve ion electrospray) m/z 197 (MH+).

(e) 2-Oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine-7-carboxaldehyde

The alcohol (13d) (1.22 g) was oxidised with manganese dioxide by themethod of Example (4c) to afford a solid (0.7 g).

MS (−ve ion electrospray) m/z 193 (M−H⁻).

(f) Title Compound

This was prepared from amine (1e) (200 mg) and carboxaldehyde (13e) (129mg) by the method of Example (4d) to provide the free base of thedesired compound as a colourless solid (138 mg).

δH (CDCl₃/CD₃OD 250 MHz), 8.65 (1H, d), 8.52 (1H, d), 8.22 (1H, d), 8.10(1H, d), 7.28 (1H, d), 7.21 (1H, d), 4.15 (3H, s), 3.90 (2H, s), 3.60(2H, s), 2.74 (1H, m), 2.52 (1H, m), 2.20 (4H, m), 1.70 (2H, m) 1.40(2H, m). MS (+ve ion electrospray) m/z 479 MH+).

The oxalate salt was prepared by the method of Example 1

Example 14Trans-4-[(2-Oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazin-7-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-quinolin-4-yl)-amide oxalate salt

This was prepared from amine (11c) (200 mg) and carboxaldehyde (13e)(129 mg) by the method of Example (4d) to provide the free base of thedesired compound as a colourless solid (43 mg).

δH (CDCl₃/CD₃OD 250 MHz), 8.55 (1H, d), 8.07 (1H, d), 8.02 (1H, d), 7.90(1H, d), 7.43 (1H, d), 7.38 (1H, dd), 7.30 (1H, d), 3.97 (3H, s), 3.90(2H, s), 3.55 (2H, s), 2.60 (2H, m), 2.10 (4H, m), 1.70 (2H, m) 1.30(2H, m). MS (+ve ion electrospray) m/z 478(MH+).

The oxalate salt was prepared by the method of Example 1

Example 15Trans-4-[(3,4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide oxalate salt

(a) (3,4-Dihydro-2H-benzo[1,4]oxazin-6-yl)-methanol

A solution of carboxaldehyde (8b) (1.45 g) in dry tetrahydrofuran (100mL) was treated with a 1M solution of lithium aluminium hydride indiethyl ether (24 mL) and the mixture was heated under reflux for 18hours. It was cooled and a solution of saturated sodium carbonate wasadded cautiously. Chloroform was added and anhydrous sodium sulfate andthe mixture was stirred for 1 hour and filtered. The fitrate wasevaporated to afford a white solid (0.70 g).

MS (−ve ion electrospray) m/z 164(M−H⁻).

(b) 3,4-Dihydro-2H-benzo[1,4]oxazine-6-carboxaldehyde and4H-benzo[1,4]oxazine-6-carboxaldehyde

A solution of the alcohol (15a) (0.22 g) in dichloromethane (10 mL) wasstirred with manganese dioxide (0.6 g) for 6 hours. It was thenfiltered, evaporated and chromatographed on silica gel, eluting withchloroform, to give a mixture of two aldehydes as an oil (90 mg).

MS (+ve ion electrospray) m/z 162 and 164 (MH⁺)

(c) Title Compound

This was prepared from amine (1e) (165 mg) and the mixture ofcarboxaldehydes (15b) (90 mg) by the method of Example (4d). The productin tetrahydrofuran (15 mL) and methanol (15 mL) was treated with sodiumcyanoborohydride (25 mg) for 18 hours. The mixture was evaporated,treated with water and extracted with chloroform-methanol (99:1), dried(sodium sulfate), evaporated and chromatographed on silica gel(chloroform then methanol-dichloromethane) to provide the title compound(free base) as a colourless solid (55 mg).

δH (CDCl₃/CD₃OD 250 MHz), 8.65 (1H, d), 8.50 (1H, d), 8.18 (1H, d), 7.22(1H, d) 6.75 (2H, m), 6.60 (1H, dd), 4.25 (1H, m), 4.15 (3H, s), 3.92(2H, s), 3.40 (4H, m), 3.00 (1H, m), 2.65 (1H, m), 2.25 (4H, m), 1.70(4H, m). MS (+ve ion electrospray) m/z 448(MH+).

The oxalate salt was prepared by the method of Example 1

Example 16Trans-4-[(Thiazolo[5,4-b]-pyridin-6-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide oxalate salt

(a) 5-Amino-6-thioxo-1,6-dihydro-pyridine-3-carboxylic acid methyl ester

A mixture of sodium sulfide nonahydrate (2.17 g) and sulfur (0.29 g) washeated in boiling water (20 mL) until the solution was homogeneous andadded to a solution of 6-chloro-5-nitro-nicotinic acid methyl ester (seeExample 13a) (3.10 g) in methanol (50 mL) The mixture was boiled for 15minutes and cooled. The resulting disulfide was collected and washedwith water to give a yellow solid (2.46 g). The solid (5 g) in aceticacid (100 mL) and 4M HCl in dioxan (50 mL) was treated with zinc dust(12 g) and the mixture was stirred at room temperature for 30 minutes,filtered and evaporated to dryness. Sodium acetate and sodium sulfatewere added and the mixture was extracted with warm chloroform andchromatographed on silica gel, eluting with chloroform thenmethanol-chloroform to afford a yellow solid (2.3 g).

MS (+ve ion electrospray) m/z 185(MH+)

(b) Thiazolo[5,4-b]pyridine-6-carboxylic acid methyl ester

The amine (16a) (0.7 g) was heated in formic acid (30 mL) under refluxfor 30 minutes and was evaporated and chromatographed on silica gel(chloroform) to give a solid (0.65 g).

MS (+ve ion electrospray) m/z 195(MH+)

(c) Thiazolo[5,4-b]pyridin-6-yl-methanol

A solution of ester (16b) (200 mg) in dry tetrahydrofuran (15 mL) anddry diethyl ether (15 mL), cooled to −45° C., was treated with a 1Msolution of lithium aluminium hydride in diethyl ether (1.55 mL) and themixture was heated under reflux for 18 hours. It was cooled and anaqueous solution of saturated sodium carbonate was added cautiously.Dichloromethane and anhydrous sodium sulfate were added and the mixturewas stirred for 15 minutes and filtered. The fitrate was evaporated toafford a white solid (95 mg).

MS (+ve ion electrospray) m/z 167(MH+)

(d) Thiazolo[5,4-b]pyridine-6-carboxaldehyde

The alcohol (16c) (65 mg) in chloroform (10 mL) was stirred withmanganese dioxide (200 mg) for 5 hours, filtered and evaporated andchromatographed on silica gel, eluting with dichloromethane thenchloroform, to give a solid (65 mg).

MS (+ve ion electrospray) m/z 165(MH+)

(e) Title Compound

This was prepared from amine (1e) (181 mg) and carboxaldehyde (16d) (90mg) by the method of Example (4d) to provide the free base of thedesired compound as a colourless solid (89 mg).

δH (CDCl₃ 250 MHz), 9.50 (1H, br.s) 9.15 (1H, s), 8.70 (2H, m), 8.55(1H, d), 8.38 (1H, d), 8.25 (1H, d), 7.16 (1H, d), 4.12 (3H, s), 4.10(2H, s), 2.70 (1H, m), 2.48 (1H, m), 2.20 (4H, m), 1.70 (2H, m) 1.40(2H, m). MS (+ve ion electrospray) m/z 449(MH+).

The oxalate salt was prepared by the method of Example 1

Example 17Trans-4-[(8-Hydroxy-1-oxo-1,2-dihydro-isoquinolin-3-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide dihydrochloride salt

(a) Ethyl 2-methoxymethoxy-6-methylbenzoic acid

A solution of ethyl 2-hydroxy-6-methylbenzoic acid (4.56 g, 25.3 mmol)and diisopropylethylamine (13.2 mL, 76 mmol) in dry dichloromethane (30mL) was cooled in an ice-bath. Chloromethyl methyl ether (3.83 mL, 50.6mmol) was added slowly and the mixture was allowed to stand at 0° C.,warming slowly to room temperature. After 36 hours a further portion ofchloromethyl methyl ether (1.9 mL) was added and the mixture was left atroom temperature overnight. The mixture was then washed with 10% citricacid, water and brine, dried and evaporated to give the title compound(6.34 g, 100%).

MS (+ve ion electrospray) m/z 225 (MH+).

(b) 8-Methoxymethoxy-1-oxo-1H-isochromene-3-carboxylic acid ethyl ester

n-Butyllithium (1.6M in hexanes, 16.0 mL, 25.5 mmol) was added to asolution of diisopropylamine (3.64 mL, 25.5 mmol) andN,N,N′,N′-tetramethylethylenediamine (4.01 mL, 25.5 mmol) in drytetrahydrofuran (36 mL) at −78° C. After 10 min a solution of the ester(17a, 5.10 g, 22.8 mmol) in dry tetrahydrofuran (18 mL) was addeddropwise, keeping the internal temperature <−60° C. The deep redsolution was stirred at −78° C. for 40 min, then diethyl oxalate (3.10mL, 22.8 mmol) in tetrahydrofuran (18 mL) was added over 5 min. Themixture was stirred at −78° C. for 6.5 hours, then treated with 10%citric acid. After warming to room temperature the phases were separatedand the aqueous phase was extracted with ethyl acetate. The combinedorganic phases were washed with brine, dried and evaporated.Chromatography on silica gel (20-40% ethyl acetate/hexane) gave thetitle compound (2.05 g, 32%).

MS (+ve ion electrospray) m/z 235 (loss of methoxymethyl from MH+).

(c) 8-Methoxymethoxy-1,2-dihydro-1-oxo-isoquinoline-3-carboxylic acidethyl ester

The isochromene (17b, 2.04 g, 7.34 mmol) was heated under reflux withammonium acetate (4.99 g) in ethanol (200 mL) for 24 hours. Solvent wasevaporated and the residue was dissolved in ethyl acetate and water. Theaqueous phase was extracted with ethyl acetate and combined organicswere washed with water, dried and evaporated. Chromatography on silicagel (50-100% ethyl acetate/hexane) gave impure product and recoveredisochromene. The latter was treated again with ammonium acetate (1.3 g)in refluxing ethanol (50 mL) for 48 hours, then worked up as before. Thecrude material was combined with the initial impure product forchromatography on silica gel (0-2% methanol/dichloromethane). Elutedmaterial was re-chromatographed (50-100% ethyl acetate/hexane) to givethe title compound (0.87 g, 42%).

MS (+ve ion electrospray) m/z 278 (MH+).

(d) 8-Hydroxy-3-hydroxymethyl-2H-isoquinolin-1-one

The ester (17c, 0.66 g, 2.38 mmol) and sodium borohydride (0.14 g, 3.6mmol) were heated in refluxing tert-butanol (3 mL) while methanol (0.6mL) was added over 1 hour. Heating was continued for 2 hours, then thecooled mixture was partitioned between ethyl acetate and water. Theaqueous phase was re-extracted with ethyl acetate and the combinedorganics were washed with brine, dried and evaporated to give the titlecompound (0.51 g, 91%).

MS (+ve ion electrospray) m/z 236 (MH+).

(e) 8-Methoxymethoxy-1,2-dihydro-1-oxo-isoquinoline-3-carboxaldehyde

The alcohol (17d, 0.51 g, 2.17 mol) was stirred with manganese (IV)oxide (3.12 g) in 1:1 dichloromethane/tetrahydrofuran (40 mL) at roomtemperature for 5 hours. The mixture was filtered and evaporated to givethe aldehyde (0.32 g, 63%).

MS (−ve ion electrospray) m/z 232 (M−H⁻).

(f)4-[(8-Methoxymethoxy-1-oxo-1,2-dihydro-isoquinolin-3-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide

The aldehyde (17e, 0.23 g, 0.99 mol) and amine (1e, 0.30 g, 1 mmol) wereheated with 3 Å molecular sieves under reflux in dry chloroform (8 mL)and methanol (1 mL) for 7 hours. After cooling, sodiumtriacetoxyborohydride (1.06 g, 5 mmol) was added and the mixture wasstirred at room temperature for 3 days. Water and dichloromethane wereadded, the aqueous phase was basified with sodium carbonate andextracted with dichloromethane. Combined organics were washed withwater, dried and evaporated. Chromatography on silica gel (2-10%methanol/dichloromethane) gave the title compound (0.157 g, 30%).

MS (+ve ion electrospray) m/z 518 (MH+).

(g) Title Compound

The methoxymethyl compound (17f, 0.157 g, 0.3 mmol) was partiallydissolved in 5M hydrochloric acid (10 mL) and 1,4-dioxane (10 mL) andstirred at room temperature for 3.5 hours. Evaporation to dryness gavethe title compound (0.16 g, 98%).

δH (CDCl₃, 250 MHz), 12.88 (1H, br s), 11.92 (1H, s), 10.30 (1H, s),9.69 (1H, br s), 8.91 1H, d), 8.68 (1H, d), 8.50 (1H, d), 7.59 (2H, m),7.09 (1H, d), 6.92 (1H, s), 6,86 (1H, d), 4.24 (3H, s), 4.16 (2H, m),3.19 (1H, m), 2.29 (1H, m), 2.26 (2H, m), 2.15 (2H, m), 1.59 (4H, m). MS(+ion electrospray) m/z: 474 (MH⁺).

Example 18Trans-4-[(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-6-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide oxalate salt

(a) 2-(2-Iodo-6-methyl-pyridin-3-yloxy)-ethanol

2-Iodo-6-methyl-pyridin-3-ol (6.49 g, 27.6 mmol) was dissolved in anaqueous solution of sodium hydroxide (1M, 30 mL). 2-bromoethanol (3.91mL, 55.2 mmol) was added dropwise and then the solution was heated to100° C. for 3 hours. The resulting mixture was extracted with chloroform(2×200 mL) and the combined organic phases then back extracted withaqueous sodium hydroxide solution (1M, 50 mL). The organic phase wasdried over magnesium sulfate and the volatiles removed in vacuo toafford the desired product (5.26 g) which was used without furtherpurification.

MS (APCI+) m/z 210 (MH+).

(b) 6-Methyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine

Alcohol (18a) (6.52 g, 23.37 mmol) was dissolved inN,N′-dimethylformamide (30 mL) and cooled to 0° C. To this was addedsodium hydride (60% w/w, 1.12 g, 28.04 mmol), powdered copper (0.62 g,9.82 mmol) and copper(II)sulfate (1.87 g, 11.69 mmol). The resultingslurry was heated to 100° C. for 18 hours and then the solvent removedunder reduced pressure. The residue was partitioned between ethylacetate (2×100 mL) and water (25 mL). The organic phases were combinedand dried over magnesium sulfate then the volatiles removed in vacuo.The residue was subjected to purification on silica gel using adichloromethane and methanol gradient. This afforded the desired productas a brown crystalline solid (480 mg, 14%).

MS (APCI+) m/z 152 (MH+).

(c) 6-Methyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-N-oxide

Pyridyldioxin (18b) (190 mg, 1.26 mmol) was dissolved in dichloromethane(10 mL) and cooled to 0° C. To this solution was addedmeta-chloroperbenzoic acid (388 mg, 1.26 mmol) and stirring wascontinued for 5 hours at room temperature. The volatiles were removedunder reduced pressure and the residue purified on silica gel using adichloromethane and methanol gradient. This provided the desiredcompound as a white solid (146 mg, 69%).

MS (APCI+) m/z 168 (MH+).

(d) Acetic Acid 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-ylmethyl ester

N-oxide (18c)(146 mg, 0.874 mmol) was dissolved in acetic anhydride (5mL). The solution was heated to reflux for 10 hours after which time thevolatiles were removed. This afforded the desired product which was usedwithout further purification.

(e) (2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-methanol

Ester (18d) (182 mg, 0.87 mmol) was dissolved in a mixture oftetrahydrofuran and water (1:1, 4 mL) and treated with sodium hydroxide(70 mg, 1.74 mmol). The resulting solution was stirred at roomtemperature for 12 hours after which time the solvent was removed underreduced pressure. The product obtained in this fashion was used withoutfurther purification.

(f) 2,3-Dihydro-[1,4]dioxino[2,3-b]pyridine-6-carbaldehyde

Alcohol (18e) (145 mg, 0.87 mmol) was dissolved in dichloromethane (5mL) and treated with manganese dioxide (151 mg, 1.74 mmol). Theresulting slurry was stirred at room temperature and after 5 hours afurther batch of manganese dioxide (151 mg, 1.74 mmol) was added. Theslurry was stirred for a further 10 hours and then filtered throughCelite and the volatiles removed in vacuo. The residue was purified onsilica gel to afford the desired product (95 mg, 66%).

MS (APCI+) m/z 166 (MH+).

(g) Title Compound

This was prepared from amine (1e) (260 mg, 0.864 mmol) andcarboxaldehyde (18f) (95 mg, 0.576 mmol) by the method of Example (4d)to provide the free base of the desired compound as a colourless solid(220 mg, 85%).

δH (CDCl₃, 250 MHz), 9.48 (1H, s), 8.67 (1H, d), 8.50 (1H, d), 8.24 (1H,d), 7.18 (1H, d), 7.14 (1H, d), 6.91 (1H, d), 4.45 (2H, m), 4.27 (2H,m), 4.13 (3H, s), 3.99 (2H, s), 2.76 (1H, m), 2.45 (1H, m), 2.20-2.15(4H, m), 1.74-1.51 (4H, m). MS (+ve ion electrospray) m/z 450 (MH+).

The oxalate salt was prepared by the method of Example 1.

Example 19Trans-4-[(2,3-Dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide oxalate salt

(a) 4,5-Dihydroxy-pyridine-2-carboxylic acid ethyl ester

4,5-Dihydroxy-pyridine-2-carboxylic acid (844 mg, 5.45 mmol) wasdissolved in ethanol (20 mL). Gaseous hydrochloric acid was bubbledthrough the mixture for 5 minutes whilst it was cooled in an ice bath.The solution was then heated to reflux for 2 hours. This procedure wasrepeated a further two times and then the mixture heated for 24 hours.The volatiles were removed in vacuo and water added (5 mL). This wasalso removed under reduced pressure. The hydrochloride salt of thedesired product was produced in this way and used without furtherpurification.

MS (APCI+) m/z 184 (MH+).

(b) 2,3-Dihydro-[1,4]dioxino[2,3-c]pyridine-7-carboxylic acid ethylester

Ester (19a) (540 mg, 2.95 mmol) was dissolved in N,N′-dimethylformamideand potassium carbonate (1.22 g, 8.85 mmol) was added. The mixture wasslurried by stirring rapidly and 1,2-dibromoethane (0.51 mL, 5.90 mmol)was added. The reaction was heated to 70° C. for 10 hours after whichtime the solvent was removed under reduced pressure. The residue wassubjected to column chromatography on silica gel using a dichloromethaneand methanol gradient. This provided the desired compound as a brownsolid (284 mg, 46%).

MS (APCI+) m/z 210 (MH+).

(c) (2,3-Dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl)-methanol

Pyridyldioxin (19b) (284 mg, 1.36 mmol) was dissolved in tetrahydrofaran(10 mL) and cooled to −30° C. A solution of lithium aluminium hydride(1M, 2.72 mL, 2.72 mmol) was added dropwise. The solution was allowed towarm to room temperature over 2 hours after which time the reaction wasquenched by the addition of water (2 mL). The volatiles were removed invacuo and the residue partitioned between ethyl acetate/chloroform(2×200 mL) and a saturated solution of sodium hydrogen carbonate (20mL). The organic phases were combined and dried over magnesium sulfate.The solvent was removed under reduced pressure and the residue purifiedon silica gel using a methanol and dichloromethane solvent gradient.This provided the desired compound as a colourless oil (98 mg, 43%).

MS (APCI+) m/z 168 (MH+).

(d) 2,3-Dihydro-[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde

Alcohol (19c) (98 mg, 0.587 mmol) was dissolved in dichloromethane (10mL) and manganese dioxide (152 mg, 1.76 mmol) was added. The slurry wasstirred at room temperature for 3 hours and then another batch ofmanganese dioxide (152 mg, 1.76 mmol) added. After 10 hours furtherstirring at room temperature the oxidant was removed by filtrationthrough Celite and the solvent removed under reduced pressure to providethe desired product which was used without further purification.

MS (APCI+) m/z 166 (MH+).

(e) Title Compound

This was prepared from amine (1e) (176 mg, 0.587 mmol and aldehyde (19f)(65 mg, 0.392 mmol) by the method of Example (4d) to provide the freebase of the desired compound as a colourless solid (120 mg, 68%).

δH (CDCl₃, 250 MHz), 9.47 (1H, s), 8.69 (1H, d), 8.53 (1H, d), 8.25 (1H,d), 8.08 (1H, s), 7.16 (1H, d), 6.87 (1H, s), 4.40-4.30 (4H, m), 4.13(3H, s), 4.04 (2H, s), 2.77 (1H, m), 2.48 (1H, m), 2.30-2.06 (4H, m),1.69-1.57 (4H, m). MS (+ve ion electrospray) m/z 450 (MH+).

The oxalate salt was prepared by the method of Example 1.

Example 20Trans-4-[(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-7-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide oxalate salt

(a) 5-Bromo-pyridine-2,3-diol

This compound was made according to the procedure of Dallacker, F;Fechter, P; Mues, V Journal Z. Naturforsch, 1979, 34b, 1729-1736 from2-furaldehyde.

MS (APCI+) m/z 190/192 (MH+).

(b) 7-Bromo-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine

Diol (20a) (13.50 g, 71.43 mmol) was treated in a similar manner toExample (19b) to obtain the desired compound as a brown oily solid (1.14g, 7%).

MS (APCI+) m/z 216/218 (MH+).

(c) 2,3-Dihydro-[1,4]dioxino[2,3-b]pyridine-7-carboxylic Acid ButylEster

Bromide (20b) was slurried in butanol at room temperature and degassedwith a stream of carbon monoxide gas for 10 minutes.1,8-diazabicyclo[5.4.0]undec-7-ene (0.50 mL, 3.38 mmol), palladiumdichloride (30 mg, 0.169 mmol) and 1,3-bis(diphenylphosphino)propane(139 mg, 0.338 mmol) was added. The mixture was heated to 100° C. underan atmosphere of carbon monoxide for 12 hours. The volatiles were thenremoved under reduced pressure and the residue partitioned between ethylacetate (2×100 mL) and water (20 mL). The organic phases were combinedand dried over magnesium sulfate. The solvent was once again removed invacuo and the residue subjected to purification on silica gel employingan ethyl acetate and hexane solvent gradient. This provided the desiredproduct as a colourless oil (0.436 g, 54%).

MS (APCI+) m/z 238 (MH+).

(d) (2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)-methanol

Ester (20c) was dissolved in tetrahydrofuran (10 mL). The solution wascooled to 0° C. and a solution of lithium aluminium hydride intetrahydrofuran (1M, 3.68 mL, 3.68 mmol) was added dropwise. Thereaction was stirred at 0° C. for 1 hour and then quenched by theaddition of water (2 mL). The volatiles were removed in vacuo and theresidue partitioned between ethyl acetate (3×100 mL) and water (20 mL).The organic phases were combined and concentrated to provide the desiredcompound which was used-without further purification (320 mg).

MS (APCI+) m/z 168 (MH+).

(e) 2,3-Dihydro-[1,4]dioxino[2,3-b]pyridine-7-carbaldehyde

The alcohol (20d) was transformed into an aldehyde according to theprocedure used in Example (19d). This provided the desired compound as acolourless oil (282 mg, 89%).

MS (APCI+) m/z 166 (MH+).

(f) Title Compound

This was prepared from amine (1e) (252 mg, 0.836 mmol) and aldehyde(20e) (138 mg, 0.836 mmol) by the method of Example (4d) to provide thefree base of the desired compound as a colourless solid (195 mg, 52%).

δH (CDCl₃, 250 MHz), 9.50 (1H, s), 8.67 (1H, d), 8.51 (1H, d), 8.25 (1H,d), 7.79 (1H, d), 7.30 (1H, d), 7.15 (1H, d), 4.50 (2H, m), 4.27 (2H,m), 4.13 (3H, s), 3.84 (2H, s), 2.73 (1H, m), 2.48 (1H, m), 2.20-2.10(4H, m), 1.72-1.60 (2H, m), 1.55-1.40 (2H, m). MS (+ve ion electrospray)m/z 450 (MH+).

The oxalate salt was prepared by the method of Example 1.

Example 21Trans-6-({4-[2-Hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-cyclohexylamino}-methyl)-4-H-benzo[1,4]thiazin-3-oneoxalate salt

(a)2-(4-tert-Butoxycarbonylamino-cyclohexyl)-3-(6-methoxy-quinolin-4-yl)-3-oxo-propionicacid methyl ester

(4-Tert-Butoxycarbonylamino-cyclohexyl)-acetic acid methyl ester (1.00g, 3.69 mmol) was dissolved in tetrahydrofuran (20 mL) and cooled to−78° C. To the solution lithium hexamethyldisilazide in tetrahydrofuran(1M, 11.0 mL, 11.0 mmol) was added dropwise. The reaction mixture wasstirred for 20 minutes at −78° C. and then6-methoxy-quinoline-4-carboxylic acid methyl ester (1.60 g, 7.38 mmol)was added as a solution in tetrahydrofuran (10 mL). The mixture wasallowed to warm to room temperature and stirred for 12 hours. Thereaction was quenched by the addition of water (2 mL), the solventremoved in vacuo and the residue partitioned between ethyl acetate(2×100 mL) and water (20 mL). The pH of the aqueous phase was adjustedto 10 to obtain the maximum degree of extracted material into theorganic phases. The organic phases were combined, dried over magnesiumsulfate and the volatiles removed under suction. The resulting residuewas purified by column chromatography on silica gel using an ethylacetate and hexane solvent gradient to provide the desired compound as acolourless oil (190 mg, 12%).

MS (APCI+) m/z 457 (MH+).

(b) 2-(4-Amino-cyclohexyl)-1-(6-methoxy-quinolin-4-yl)-ethanonehydrochloride

Ketone (21a) (190 mg, 0.42 mmol) was dissolved in an aqueous solution ofhydrochloric acid (5M, 10 mL). The solution was refluxed under argon for5 hours and then the volatiles were removed in vacuo. This provided thedesired product as a hydrochloride salt (154 mg).

MS (APCI+) m/z 299 (MH+).

(c) {4-[2-(6-Methoxy-quinolin-4-yl)-2-oxo-ethyl]-cyclohexyl}-carbamicacid tert-butyl ester

Amine hydrochloride (21b) (2.77 g, 8.28 mmol) was dissolved indichloromethane (20 mL), triethylamine (3.46 mL, 24.84 mmol) was thenadded. Di-tert butyl dicarbonate (1.80 g, 8.28 mmol) was added to thesolution and the reaction mixture stirred at room temperature for 6hours. The organic phase was extracted with a saturated solution ofsodium hydrogen carbonate (20 mL). The organic phase was dried overmagnesium sulfate and the volatiles removed in vacuo. The residue waspurified on silica gel using a dichloromethane and methanol solventgradient. This provided the desired product as a colourless oil.

MS (APCI+) m/z 399 (MH+).

(d){4-[2-Hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-cyclohexyl}-carbamicacid tert-butyl ester

Ketone (21c) (862 mg, 2.17 mmol) was dissolved in iso-propanol (10 mL)and the solution cooled to 0° C. To this, sodium borohydride (125 mg,3.25 mmol) was added and the resulting slurry stirred at 0° C. for 3hours. The volatiles were removed under reduced pressure and the residuepartitioned between ethyl acetate (2×100 mL) and water (20 mL). Theorganic phases were combined and dried over magnesium sulfate and thenthe solvent removed in vacuo. This provided the desired compound whichwas used without further purification.

MS (APCI+) m/z 401 (MH+).

(e) Title Compound

Alcohol (21d) was dissolved in dichloromethane, cooled to 0° C. andtreated with trifluoroacetic acid. The solution was stirred at roomtemperature for 3 hours and then concentrated under vacuum. The residuewas treated with an aqueous solution of sodium hydroxide (1M, 10 mL) andthen concentrated in vacuo. The residue was dissolved in chloroform (10ml) and methanol (5 mL), aldehyde (4c) (170 mg; 0.825 mmol) added, andthe mixture was heated at reflux with 3 Å molecular sieves (2 g) for 12hours. The slurry was then cooled and sodium triacetoxyborohydride (525mg, 2.48 mmol) adde. This was stirred at room temperature for 48 hours.The slurry was filtered through Celite and concentrated in vacuo. Theresidue was purified by column chromatography on silica gel employing adichloromethane and methanol solvent gradient. This provided the desiredproduct as a white solid (226 mg, 57%).

δH (CD₃OD, 250 MHz), 8.66 (1H, d), 7.95 (1H, d), 7.66 (1H, d), 7.44-7.33(3H, m), 7.13 (1H, dd), 7.07 (1H, d), 5.50 (1H, m), 4.18 (2H, s), 3.95(3H, s), 3.44 (2H, s), 3.14-3.09 (1H, m), 2.36-2.19 (3H, m), 1.91-1.65(4H, m), 1.55-1.40 (2H, m), 1.25-1.05 (2H, m). MS (APCI+) m/z 478(MH+).

The oxalate salt was prepared by the method of Example 1.

Example 22Trans-2-{4-[(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-cyclohexyl}-1-(6-methoxy-quinolin-4-yl)-ethanoloxalate salt

(a)2-{4-[(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-cyclohexyl}-1-(6-methoxy-quinolin-4-yl)-ethanone

Amine hydrochloride (21b) (233 mg, 0.697 mmol) was dissolved inN,N′-dimethylformamide (5 mL). To the solution potassium carbonate (289mg, 2.09 mmol) was added followed by mesylate (5b) (256 mg, 1.045 mmol).The mixture was stirred at room temperature for 10 hours and then thevolatiles were removed in vacuo. The residue was purified by columnchromatography on silica gel using a methanol and dichloromethanesolvent gradient. This provided the desired product as a colourless oil(42 mg, 14%).

MS (APCI+) m/z 447(MH+).

(b) Title Compound

Ketone (22a) was dissolved in iso-propanol (1 mL) and cooled to 0° C.The solution was treated with sodium borohydride (7 mg, 0.168 mmol).Stirring was continued at room temperature for 10 hours and then thevolatiles removed under reduced pressure. The residue was purified onsilica gel using a dichloromethane and methanol solvent gradient. Thisprovided the free base of the desired compound as a colourless oil. (25mg, 50%).

δH (CDCl₃, 250 MHz), 8.71 (1H, d), 8.01 (1H, d), 7.55 (1H, d), 7.36 (1H,dd), 7.15 (1H, d), 6.76 (3H, m), 5.42 (1H, dd), 4.22 (4H, s), 3.92 (3H,s), 3.69 (2H, s), 2.59 -2.50 (2H, m), 2.21-2.08 (1H, m), 2.08-1.95 (2H,m), 1.85-1.60 (4H, m), 1.35-1.20 (2H, m), 1.17-1.00 (2H, m). MS (APCI+)m/z 449 (MH+).

The oxalate salt was prepared according to the method in Example 1.

Example 23Trans-4-[(6-Nitro-benzo[1,3]dioxol-5-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide oxalate salt

A solution of amine (1e) (0.3 g, 1 mmol) and6-nitro-benzo[1,3]dioxole-5-carbaldehyde (0.21 g, 1.1 mmol) inchloroform/methanol (2 ml/1 ml) was stirred for 1 h. The resultingprecipitate (imine) was dissolved by the addition of more methanol (3ml) and treated with sodium borohydride (80 mg, 2.2 mmol). After 1 h themixture was partitioned between chloroform and water. The organicextract was dried and evaporated to give an oil (0.4 g). Chromatographyon silica eluting with a methanol-ethyl acetate gradient afforded thefree base of the title compound (0.16 g, 33%).

δH (CDCl₃, 250 MHz), 9.50 (1H, bs), 8.70 (1H, d), 8.55 (1H, d), 8.20(1H, d), 7.50 (1H, d), 7.15 (1H, d), 7.10 (1H, s), 6.10 (2H, s), 4.15(3H, s), 4.00 (2H, s), 2.65-2.60 (1H, m), 2.40-2.35 (1H, m), 2.20-2.10(4H, m), 1.80-1.60 (2H, m), 1.30-1.20 (2H, m). MS (+ve ion electrospray)m/z 480 (MH+).

This was converted to the oxalate salt according to the procedure ofExample 1.

Example 24Trans-4-[(6-Amino-benzo[1,3]dioxol-5-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide dioxalate salt

This was prepared from nitro compound (23a) (100 mg, 0.223 mmol) byhydrogenation in the presence of 10% palladium metal on a carbon support(20 mg). After 5 hours the catalyst was removed by filtration throughCelite and the solvent removed under reduced pressure. The residue waspurified by column chromatography on silica gel using a methanol anddichloromethane solvent gradient. This provided the free base of thedesired compound as a colourless oil (56 mg, 60%).

δH (CDCl₃, 250 MHz), 9.50 (1H, s), 8.70 (1H, d), 8.51 (1H, d), 8.22 (1H,d), 7.16 (1H, d), 6.59 (1H, s), 6.29 (1H, d), 5.86 (2H, s), 4.12 (3H,m), 3.78 (2H, s), 2.60 (1H, m), 2.43 (1H, m), 2.21-2.15 (4H, m),1.75-1.61 (2H, m), 1.32-1.26 (2H, m). MS (APCI+) m/z 450 (MH+).

The dioxalate salt was prepared by a method analogous to that of Example1.

Example 25Trans-4-[(Benzothiazol-5-ylmethyl)-amino]cyclohexanecarboxylicacid(6-methoxy-[1,5]naphthyridine-4-yl)amide oxalate salt

(a) Benzothiazol-5-ylcarboxylic acid

4-Chloro-3-nitrobenzoic acid (22 g, 0.11 mol) was suspended in water,sodium hydroxide (4.33 g, 0.11 mol) and sodium sulfide hydrate (32 g)were added, and the mixture heated at reflux for 24 hours. Afteracidification with 5M hydrochloric acid the mixture was extracted withethyl acetate. The extracts were dried over magnesium sulfate andevaporated under reduced pressure. The product from this reaction (1 g,5.9 mmol) was dissolved in formic acid and heated at reflux in thepresence of zinc (0.1 g) for 6 hours. The mixture was allowed to cooland was concentrated under reduced pressure. The residue was dilutedwith water and neutralised with saturated aqueous sodium hydrogencarbonate. Extraction with tetrahydrofuran and ethyl acetate (1:1) gavea pale yellow solid (0.48 g) that was purified on silica gel using amethanol dichloromethane gradient.

(b) Benzothiazol-5-ylcarbaldehyde.

This was prepared from carboxylic acid 23(b) by the method of 4(b) and(c).

δH (CDCl₃ 250 MHz), 10.17 (1H, d), 9.14 (1H, s), 8.60 (1H, d), 8.12 (1H,d), 8.00 (1H, dd),

(c) Title Compound

Amine (1e) (0.20 g, 0.66 mmol) and benzothiazol-5-ylcarbaldehyde (0.11g, 0.67 mmol) were heated at reflux in methanol (1 mL) and chloroform (4mL) in the presence of 3 Å sieves for 8 hours. The mixture was thencooled to room temperature and sodium triacetoxyborohydride (0.4 g)added. After 24 hours further sodium triacetoxyborohydride (0.3 g) wasadded and a further addition (0.2 g) was made after another 8 hours.After stirring for 14 hours the mixture was diluted with methanol andsolid sodium hydrogen carbonate added. After stirring for 0.25 hours themixture was filtered and evaporated. Purification on silica gel elutingwith methanol dichloromethane mixtures gave the free base of the titlecompound (0.143 g, 48%).

δH (CDCl₃,250 MHz), 9.45 (1H, s), 9.02 (1H, s), 8.68 (1H, d), 8.58-8.39(2H,m), 8.26 (1H, d), 8.17 (1H, d), 7.97 (1H, d), 7.54 (1H, dd), 7.17(1H, d), 4.20-4.07 (2H, m), 4.13 (3H, s), 2.95-2.80 (1H, m), 2.53-237(1H, m), 2.33-2.00 (4H, m), 1.72-1.49 (4H, m). MS (APCI+) m/z 448 (MH+).

The oxalate salt was prepared by the method of Example 1.

Example 26 Trans-4-[(4-Oxo-4 Hpyrido[1,2-a]pyrimidin-2-ylmethyl)-amino]-cyclohexanecarboxylic acid(6-methoxy-[1,5]naphthyridin-4-yl)-amide oxalate salt

A mixture of amine (1e) (0.5 g, 1.7 mmol) and2-chloromethyl-pyrido[1,2-a]pyrimidin-4-one (0.32 g, 1.7 mmol) (preparedby the method of W. Boehme and K. Heinrich, Arch Pharm, 1977, 310, 26)and potassium carbonate (0.25 g, 1.8 mmol) in N,N-dimethylformamide (15ml) was heated at 40° C. for 16 h. The mixture was partitioned betweenethyl acetate and water. The organic extract was dried and evaporated.Chromatography on silica gel eluting with a methanol-ethyl acetategradient afforded the free base of the title compound as an oil (0.17 g,22%).

δH (CDCl₃, 250 MHz), 9.50 (1H, bs), 9.00 (1H, d), 8.70 (1H, d), 8.55(1H, d), 8.20 (1H, d), 7.70 (1H, m), 7.60 (1H, d), 7.20-7.10 (2H, m),6.55 (1H, s), 4.10 (3H, s), 3.90 (2H, s), 2.65-2.60 (1H, m), 2.40-2.35(1H, m), 2.20-2.10 (4H, m), 1.80-1.60 (2H, m), 1.30-1.20 (2H, m), MS(+ve ion electrospray) m/z 459 (MH+).

This was converted to the oxalate salt according to the procedure ofExample 1.

Example 27Trans-2-{4-[(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-cyclohexyl}-1-(6-methoxy-quinolin-4-yl)-ethanoneoxalate salt

Amine hydrochloride (21b) (233 mg, 0.697 mmol) was dissolved inN,N-dimethylformamide (5 mL). To this was added potassium carbonate (289mg, 2.09 mmol) and mesylate (5b) (256 mg, 1.045 mmol). The resultingslurry was stirred at room temperature for 48 hours and then the solventwas removed under reduced pressure. The residue was purified by columnchromatography on silica gel using a dichloromethane and methanolsolvent gradient. This provided the desired compound as a colourless oil(42 mg, 14%).

δH (CDCl₃, 250 MHz), 8.85 (1H, d), 8.03 (1H, d), 7.79 (1H, d), 7.55 (1H,d), 7.41 (1 H, dd), 6.87-6.82 (3H, m), 4.23 (4H, s), 3.92 (3H, s), 3.69(2H, s), 2.91 (2H, d), 2.57-2.48 (1H, m), 2.04-2.01 (2H, m), 1.91-1.86(2H, m), 1.37-1.25 (2H, m), 1.15-1.0 (2H, m). MS (+ve ion electrospray)m/z 447 (MH+).

This was converted to the oxalate salt according to the procedure ofExample 1.

Example 28 Trans4-[(3-Oxo-3,4-dihydro-2-H-benzo[1,4]thiazin-6-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-quinolin-4-yl)-amide

Amine (11c) (389 mg, 1.295 mmol) and aldehyde (4c) (250 mg, 1.295 mmol)were heated at reflux in methanol (1 mL) and chloroform (4 mL) in thepresence of 3 Å sieves for 8 hours. The mixture was then cooled to roomtemperature and sodium triacetoxyborohydride (0.83 g) added. After 24hours further sodium triacetoxyborohydride (0.55 g). After stirring for48 hours the mixture was evaporated under reduced pressure. Purificationon silica gel eluting with methanol dichloromethane mixtures gave thefree base of the title compound as a white solid (311 mg, 56%).

δH (d₆-DMSO, 250 MHz), 9.98 (1H, s), 8.62 (1H, d), 7.98 (1H, d), 7.90(1H, d), 7.60 (1H, d), 7.43 (1H, dd), 7.27 (1H, d), 7.00 (2H, m), 3.95(3H, s), 3.79 (2H, m), 3.45 (2H, s), 2.69 (1H, m), 2.50 (1H, m),2.09-1.90 (4H, m), 1.56-1.49 (2H, m), 1.37-1.23 (2H, m). MS (APCI+) m/z477 (MH+).

Example 29Trans-4-[(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-cyclohexanecarboxylicacid [6-(3-amino-propoxy)-[1,5]naphthyridin-4-yl]-amide dioxalate

(a) 8-Amino1-H-[1,5]naphthyridin-2-one hydrobromide

A suspension of amine (1c) (4.20 g, 24 mmol) in concentrated hydrobromicacid (35 mL) was heated at 120° C. for 2 h. The mixture was set aside inthe fridge for 2 h, then filtered, washing with small amounts of coldwater then diethyl ether. Drying in vacuo afforded the product as awhite solid (6.1 g, 100%).

MS (+ve ion electrospray) m/z 162 (MH+).

(b) [3-(8-Amino-[1,5]naphthyridin-2-yloxy)-propyl]-carbamic acid benzylester

A suspension of hydrobromide salt (29a) (1.2 g, 5 mmol) inN,N-dimethylformamide (10 mL) at 40° C. was treated with potassiumcarbonate (2.1 g, 15 mmol) then after 0.25 h with a solution of(3-bromo-propyl)-carbamic acid benzyl ester (2 g, 7.4 mmol) inN,N-dimethylformamide (5 mL). The mixture was heated for 4 h at 40° C.,then evaporated to dryness. The residue was partitioned between ethylacetate and dilute aqueous sodium chloride solution. The organic extractwas dried and evaporated to give a brown oil (2.2 g) This waschromatographed on silica eluting with a methanol/ethyl acetate gradientaffording the product as a clear oil (1.0 g, 57%).

MS (+ve ion electrospray) m/z 353 (MH+).

(c){4-[6-(3-Benzyloxycarbonylamino-propoxy)-[1,5]naphthyridin-4-ylcarbamoyl]-cyclohexyl}-carbamicacid tert-butyl ester

A solution of trans-4-tert-butoxycarbonylamino-cyclohexanecarboxylicacid (0.7 g, 2.8 mmol) and triethylamine (0.43 mL, 0.3 g, 3.1 mmol) inN,N′-dimethylformamide (3 mL) was treated withO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (1.1 g, 2.84 mmol). After 0.5 h the amine (29b) (1.0g, 2.84 mmol) in N,N′-dimethylformamide (7 mL) was added and the mixturewas heated at 60° C. for 22 h. The mixture was evaporated and theresidue was partitioned between ethyl acetate and dilute aqueous sodiumchloride solution. The organic extract was dried and evaporated to givea brown oil (2.1 g) This was chromatographed on silica eluting with amethanol/ethyl acetate gradient affording the product as a clear oil(0.9, 55%).

MS (+ve ion electrospray) m/z 578 (MH+).

(d)[3-(8-{[1-(4-Amino-cyclohexyl)-methanoyl]-amino}-[1,5]naphthyridin-2-yloxy)-propyl]-carbamicacid benzyl ester

A solution of (29c) (0.3 g, 0.52 mmol) in trifluoroaceticacid/dichloromethane (5 mL/5 mL) was maintained at room temperature for0.25 h then evaporated to dryness. The residue was partitioned betweenethyl acetate and saturated aqueous sodium bicarbonate solution. Theorganic extract was dried and evaporated. Chromatography on silicaeluting with a methanol/ethyl acetate gradient afforded an oil (0.15 g,60%).

MS (+ve ion electrospray) m/z 478 (MH+).

(e)(3-{8-[(1-{4-[(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-cyclohexyl}-methanoyl)-amino]-[1,5]naphthyridin-2-yloxy}-propyl)-carbamicacid benzyl ester

A solution of (29d) (0.15 g, 0.3 mmol) and2,3-dihydro-benzo[1,4]dioxine-6-carboxaldehyde (82 mg, 0.5 mmol) inmethanol/dichloromethane (0.3 mL/2.7 mL) was treated withfreshly-activated 3 Å molecular sieves and heated to reflux under argonfor 2 h. Sodium triacetoxyborohydride (0.21 g, 1 mol) was added and themixture was stirred at 40° C. for 1 h. The mixture was partitionedbetween ethyl acetate and saturated aqueous sodium bicarbonate solution.The organic extract was dried and evaporated to give a brown oil.Chromatography on silica eluting with a methanol/ethyl acetate gradientafforded an oil (105 mg, 54%).

MS (+ve ion electrospray) m/z 626 (MH+).

(f) Title Compound

A solution of (29e) (100 mg, 0.17 mmol) in ethanol (10 mL) was treatedwith 10% palladium on charcoal (50% dispersion with water, 60 mg) andhydrogenated for 2 h. More 10% palladium on charcoal (100 mg) was addedand the mixture hydrogenated for a further 2 h. Filtration andevaporation gave the free base of the product as a white solid (75 mg,90%)

δH (CD₃OD, 250 MHz), 8.65(1H, d), 8.55 (1H, d), 8.20 (1H, d), 8.03 (1H,d), 7.30 (1H, d), 7.00-6.80 (3H, m), 4.75 (2H, t), 4.25 (4H, s), 3.90(2H, s), 3.20 (2H, t) 2.90-2.70 (2H, m), 2.40-2.10 (7H, m), 1.80-1.40(3H, m). MS (APCI+) m/z 492 (MH+).

The oxalate salt (90 mg) was prepared by the method of Example 1.

Example 30 Trans-4-[(3-Oxo-3,4-dihydro-2-H-benzo[1,4]thiazin-6-ylmethyl)amino]-cyclohexanecarboxylic acid(8-fluoro-6-methoxy-quinolin-4-yl)-amide oxalate

Amine (10e) (225 mg, 0.710 mmol)was reacted aldehyde (4c) (137 mg, 0.710mmol) according to the procedure in Example 4d. This provided the freebase of the desired compound as a white solid (74 mg, 21%).

δH (d⁶-DMSO, 250 MHz), 8.64 (1H, d), 8.08 (1H, d), 7.47 (1H, m), 7.38(1H, dd), 7.25 (1H, d), 6.98-6.95 (2H, m), 3.96 (3H, s), 3.69 (2H, m),3.43 (2H, s), 2.68 (1H, m), 2.49 (1H, m), 1.98-1.90 (4H, m), 1.50-1.46(2H, m), 1.15-1.00 (2H, m). MS (APCI+) m/z 495 (MH+).

The oxalate salt was prepared by the method of Example 1.

Example 31Trans-4-[(3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide oxalate

(a) 6-Methyl-4H-pyrido[3,2-b][1,4]oxazin-3-one

A solution of 2-amino-6-methyl-pyridin-3-ol (5.7 g, 46 mmol) (preparedby reduction of 6-methyl-2-nitro-pyridin-3-ol according to the procedureof J. Kaminski et al, [J. Med. Chem, 30 (11), 2031 (1987)1 indimethylsulphoxide (60 ml) was treated with sodium hydride (44 mmol)under argon. After 0.25 hours methyl chloroacetate (4 mL, 5 g, 46 mmol)was added and the mixture heated at 100° C. for 3.5 hours. The reactionmixture was quenched with saturated aqueous ammonium chloride solution(10 mL), then partitioned between dichloromethane and water. The organicextracts were dried and evaporated and the residue was chromatographedeluting with 0-20% ethyl acetate in dichloromethane affording theproduct as a white crystalline solid (4.7 g, 62%).

MS (+ve ion electrospray) m/z 165 (MH+).

(b) 6-Methyl-4H-pyrido[3,2-b][1,4]oxazin-3-one N-oxide

A solution of (31a) (4.58 g, 28 mmol) in dichloromethane (100 mL) at 0°C. was treated with a solution of meta-chloroperbenzoic acid (8.75 g,˜55% pure, ˜28 mmol) in dichloromethane (100 mL). After 1 hour moremeta-chloroperbenzoic acid (1.7 g) was added. After a further 2 hoursthe mixture was loaded directly onto a silica gel column.Chromatography, eluting with a solvent mixture of aqueousammonia:methanol:ethyl acetate (3:27:70), afforded the product as awhite crystalline solid (3.5 g, 70%).

MS (+ve ion electrospray) m/z 181 (MH+).

(c) Acetic Acid 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylmethylester

A solution of (31 b) (3.0 g) in acetic anhydride (20 mL) was treatedwith acetyl chloride (0.14 mL) and heated to reflux overnight. Themixture was evaporated to dryness and the residue partitioned betweenethyl acetate and half saturated aqueous sodium bicarbonate solution.The ethyl acetate extract was filtered through celite and the filtrateevaporated. The residue was chromatographed eluting with a gradient of0-10% ethyl acetate in dichloromethane affording an oil (1.0 g).Analysis of this material showed it to be a 2:1 mixture of the productand starting material (31b), equivalent to 19% yield of the desiredproduct (31c).

MS (+ve ion electrospray) m/z 223 (MH+).

(d) 6-Hydroxymethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one

A solution of impure (31c) (1.0 g, equivalent to 3.5 mmol) and sodiumhydroxide (3.5 mmol) in water/dioxan (17 mL/30 mL) was stirred at roomtemperature for 3 days. Silica gel was added and the solvent wasremoved. Chromatography eluting with 0-100% ethyl acetate indichloromethane afforded the product as a white foam (0.2 g, 32%).

MS (+ve ion electrospray) m/z 181 (MH+).

(e) 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxaldehyde

A solution of (31d) (0.20 g, 1.1 mmol) inchloroform/dioxan/tetrahydrofuran (10 mL/10 mL/5 mL) was heated at 40°C. with manganese dioxide (1.5 g) for 2 hours. Filtration andevaporation afforded the product as a white solid (0.14 g, 70%).

MS (+ve ion electrospray) m/z 179 (MH+).

(f) Title Compound

A mixture of amine (1e) (210 mg, 0.7 mmol), aldehyde (31e) (0.14 g, 0.78mmol) and 3A molecular sieves in chloroform/methanol (3 mL/0.5 ml) washeated to reflux for 5 hours, then stabilised at 40° C. Sodiumtriacetoxyborohydride (0.25 g, 1.2 mmol) was added, and the mixturestirred at 40° C. for 0.5 hours. Water (2 mL) was added and theresulting white solid was isolated by filtration. This solid waspartitioned between ethyl acetate and half saturated aqueous sodiumbicarbonate solution. The ethyl acetate extract was dried and evaporatedgiving the free base of the title compound as a white solid (140 mg,43%).

δH (d6-DMSO, 250 MHz): 8.65(1H, d), 8.35 (1H, d), 8.20 (1H, d), 7.25(2H, m), 7.00 (1H, m), 4.65 (2H, s), 4.08 (3H, s), 3.65 (2H, s), 2.60(1H, m), 2.37 (1H, m), 1.90 (4H, m), 1.40 (2H, m), 1.20 (2H, m). MS (+veion electrospray) m/z 463 (MH+).

The free base was converted to the oxalate salt (170 mg) by the methodof Example 1

Example 32Trans-4-[([1,2,3]Thiadiazolo[5,4-b]pyridin-6-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide oxalate

(a) [1,2,3]Thiadiazolo[5,4-b]pyridine-6-carboxylic acid methyl ester

The amine (16a) (1.3 g) was suspended in 0.5 M hydrochloric acid (200mL) and cooled to −3° C. A solution of sodium nitrite (487 mg) in water(3 mL) was added dropwise over 10 minutes and the mixture was stirredfor 2 hours when the solid product was collected and chromatographed onsilica gel (chloroform) to afford a solid (0.90 g)

MS (+ve ion electrospray) m/z 196 (MH+)

(b) [1,2,3]Thiadiazolo[5,4-b]pyridine-6-carboxylic acid

The ester (32a) (0.94 g) was hydrolysed with aqueous sodium hydroxide intetrahydrofuran by the method of Example (4a) to afford a solid (0.84g).

MS (−ve ion electrospray) m/z 180 (M−H⁻).

(c) [1,2,3]Thiadiazolo[5,4-b]pyridin-6-yl-methanol

The carboxylic acid (32b) (0.82 g) was reacted withisobutylchloroformate and sodium borohydride by the method of Example(4b) to afford a semi-solid (0.12 g), after chromatography on silica gel(chloroform).

(d) [1,2,3]Thiadiazolo[5,4-b]pyridine-6-carboxaldehyde

The alcohol (32c) (0.10 g) was oxidised with manganese dioxide by themethod of Example (4c) to afford a solid (51 mg).

MS (+ve ion electrospray in methanol) m/z 198 (MH+for methanol adduct)

(e) Title Compound

This was prepared from amine (1e) (102 mg) and carboxaldehyde (32d) (51mg) by the method of Example (4d) (slow reduction with sodiumtriacetoxyborohydride so mixture of imine and product was retreated withextra sodium acetoxyborohydride for 72 hours) to provide the free baseof the desired compound as a colourless solid (44 mg).

δH (CDCl₃ 250 MHz), 9.50 (1H, br.s) 8.95 (1H, d), 8.89 (1H, d), 8.70(1H, d), 8.52 (1H, d), 8.25 (1H, d), 7.15 (1H, d), 4.16 (2H, s), 4.11(3H, s), 2.68 (1H, m), 2.45-2.15 (5H, m), 1.70 (2H, m), 1.35 (2H, m). MS(+ve ion electrospray) m/z 450 (MH+).

The oxalate salt was prepared by the method of Example 1

Example 33Trans-4-(3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-sulfonylamino)-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide

(a) 3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-sulfonyl chloride

Powdered 4H-benzo[1,4]thiazin-3-one (7.0 g) was added cautiously,portionwise (over 20 minutes), to chlorosulfonic acid (15 mL), cooled inice. After 1 hour the blue solution was allowed to warm to roomtemperature and it was heated at 45° C. for 2 hours, cooled and pouredinto ice. The solid was collected, washed with water, and hexane, anddried in vacuo, to give a white solid (7.0 g).

(b) Title Compound

A solution of amine (1e) (0.20 g, 0.66 mmol) in dichloromethane (20 mL)was treated with triethylamine (0.23 mL, 1.7 mmol) then the sulfonylchloride (33a) (0.28 g, 1 mmol) was added in one portion. After 1 daythe mixture was filtered, washing with dichloromethane. The resultingsolid was recrystallised from boiling methanol to afford the titlecompound as a white solid (7 mg, 2%).

δH (d₆-DMSO, 250 MHz): 10.85 (1H, bs), 9.70 (1H, bs), 8.62(1H, d), 8.38(1H, d), 8.25 (1H, d), 7.75 (1H, d), 7.50 (1H, d), 7.45-7.30 (2H, m),7.25 (1H, d), 4.10 (3H, s), 3.57 (2H, s), 2.95 (1H, m), 2.60 (1H, m),1.95 (2H, m), 1.75 (2H, m) 1.50-1.20 (4H, m) MS (+ve ion electrospray)m/z 528 (MH+).

Example 34Trans-4-[(7-Fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide oxalate salt

(a) 2,4-Difluoro-5-nitro-benzoic acid ethyl ester

2,4-Difluorobenzoic acid ethyl ester (5.33 g) was cooled to 0° C. andtreated with concentrated sulfuric acid (3.5 mL) and then fuming nitricacid (3.5 mL). The mixture was stirred for 2 hours at 0° C. and thenpartitioned between dichloromethane (2×50 mL) and water (25 mL). Theorganic phase was back extracted with water (25 mL) and then dried overmagnesium sulfate and concentrated in vacuo. This provided the desiredcompound as a white solid (5.00 g) which was used without furtherpurification.

(b) 2-Fluoro-4-methoxycarbonylmethylsulfanyl-5-nitro-benzoic acid ethylester

Ester (34a) (2.82 g, 12.21 mmol) was dissolved in dichloromethane (50mL) and triethylamine was added (2.04 mL, 14.65 mmol). The mixture wascooled to 0° C. and methyl thioglycolate (0.98 mL, 10.98 mmol) was addeddropwise. Stirring was continued at 0° C. for 3 hours after which timethe volatiles were removed in vacuo. The residue was purified by columnchromatography on silica gel using an ethylacetate and hexanes solventgradient. This provided the desired compound as a yellow solid (2.05 g).

(c) 7-Fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acidethyl ester

This was prepared by an iron mediated reductive cyclisation of nitrocompound (34b) using a method similar to Example (13b) This provided thedesired compound as a white solid (1.02 g).

(d) 7-Fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid

This was prepared by hydrolysis of ethyl ester (34c) using the method ofExample (4a) to give a white solid (1.00 g).

(e) 7-Fluoro-6-hydroxymethyl-4H-benzo[1,4]thiazin-3-one

This was prepared by reduction of the mixed anhydride of acid (34d)according to the method of Example (4b) to give the alcohol (0.93 g).m/z (APCI+) 214 (MH+).

(f) 7-Fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxaldehyde

Oxidation of alcohol (34e) with manganese dioxide was performedaccording to the procedure of Example (4c), to give the aldehyde (1.00g).

(g) Title Compound

Amine (1e) was reductively alkylated with aldehyde (34f) in the samemanner as Example (4d). This provided the free base (30 mg) of thedesired compound after purification on silica gel. The oxalate salt wasgenerated in the same fashion as Example 1

MS (APCI+) m/z 496 (MH+) δH (d6-DMSO, 250 MHz) 10.60 (1H, bs), 9.76 (1H,bs), 8.67 (1H, d), 8.39 (1H, d), 8.26 (1H, d), 7.32 (1H, d), 7.22 (1H,bm), 7.11 (1H, d), 4.14 (3H, s), 3.40 (2H, s), 3.30 (2H, s), 2.70 (1H,m), 2.54 (1H, m), 2.05 (4H, m), 1.51 (2H, m), 1.10 (2H, m). m/z (APCI+)496 (MH+).

Example 35Trans-4-[(8-Nitro-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-amino]-cyclohexanecarboxylicAcid (6-methoxy)-[1,5]naphthyridin-4-yl)-amide Oxalate

(a) 8-Nitro-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxaldehyde

The carboxaldehyde (8b) (0.18 g, 1.0 mmol) was stirred and cooled inice, while fuming nitric acid (0.1 mL) was added. The mixture wasstirred at room temperature for 3 hours then diluted with water andextracted with ethyl acetate. the extracts were washed with brine, driedand evaporated. Chromatography on silica gel (0-1% methanol indichloromethane) gave a solid (0.16 g, 71%).

(b) Title Compound

A solution of the amine (1e) (0.30 g 11.0 mmol) and aldehyde (35a) inmethanol (2 mL) and chloroform (8 mL) was stirred at 56° C. over 3Amolecular sieves for 7 hours. Sodium triacetoxyborohydride (1.04 g) wasadded and the mixture stirred at room temperature for 7 days then at 56°C. for 7 days. The mixture was diluted with methanol and solid sodiumbicarbonate added. After being stirred for 15 minutes the mixture wasevaporated and chromatographed on silica gel (2-10% methanol indichloromethane). The mixture of imine and amine (0.103 g) thus obtainedwas dissolved in methanol (2 mL) and chloroform (5 mL), sodiumtriacetoxyborohydride (0.13 g) was added and the mixture stirred at roomtemperature for 24 hours, further sodium triactoxyborohydride (0.13 g)was added and stirring continued for 24 hours. The mixture was worked upas before and chromatographed on silica gel (2-7.5% methanol in DCM) togive the title compound as the free base(0.036 g, 7%).

MS (+ve ion electrospray) m/z 507 (MH+) δH (CDCl₃, 250 MHz), 8.68 (1H,d), 8.52 (1H, d), 8.25 (1H, d), 7.77 (1H, s), 7.28 (1H, s), 7.19 (1H,d), 4.62 (2H, s), 4.36 (2H, s), 4.15 (3H, s), 2.63-2.20 (4H, m),2.18-2.00 (2H, m), 1.78 (4H, m).

The oxalate salt was prepared by the method of Example 1

A mixture of the title compound and4-[(8-nitro-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-imino]-cyclohexanecarboxylicacid (6-methoxy)-[1,5]naphthyridin-4-yl)-amide (0.059 g) was alsoobtained during chromatography.

Example 36Trans-4-[(8-Amino-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy)-[1,5]naphthyridin-4-yl)-amide Oxalate

The mixture of compound Example (35) and4-[(8-nitro-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-imino]-cyclohexanecarboxylicacid (6-methoxy)-[1,5]naphthyridin-4-yl)-amide obtained from Example(35b) (0.059 g) was dissolved in ethanol and hydrogenated over 10%palladium on charcoal for 18 hours. The mixture was filtered throughkieselguhr and evaporated. Chromatography on silica gel (5-10%methanol/DCM then 5-10% methanol/dichloromethane containing 0.5-1%NH₄OH) gave the title compound as the free base(0.13 g).

MS (+ve ion electrospray) m/z 477 (MH+) δH (CDCl₃+MeOD, 250 MHz), 8.68(1H, d), 8.51 (1H, d), 8.22 (1H, d), 7.17 (1H, d), 6.57 (1H, s), 6.33(1H, s), 4.52 (2H, s), 4.12 (3H, s), 3.79 (2H, s), 2.61 (1H, m), 2.44(1H, m), 2.19 (4H, m), 1.72 (2H, m), 1.26 (2H, m).

The oxalate salt was prepared by the method of Example 1

The following Examples were prepared by analogous methods.

A: by method of Example 29

B: by method of Example 4

salt Method G oxalate of A Hydrochloride Example synthesis R₁ LINKER AYDioxalate R 100 A 6-O(CH₂)₃NH2 NHCO G benzo[1,2,3]thiadiazol-5-yl 101 B6-OMe NHCO G 2-oxo-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazin-7-yl 102 B6-OMe NHCO G 5-nitro-3-oxo-3,4-dihydro-2H- benzo[1,4] oxazin-6-yl 103 a6-OMe NHCO G 5-amino-3-oxo-3,4-dihydro-2H- benzo[1,4] oxazin-6-yl 104 B6-OMe NHCO G 2,3-dihydro-1H-pyrido[2,3- b][1,4]oxazin-7-yl 105 A6-(OCH₂)₃NH₂ NHCO AY 4H-benzo[1,4]thiazin-3-one-6-yl 106 b 6-OMe NHCO A6-[3-oxo-2,3-dihydro- benzo[1,4]thiazin-4-yl)-acetic acid] 107 c 6-OMeNHCO G 6-[3-oxo-2,3-dihydro- benzo[1,4]thiazin-4-yl)-acetic acidtert-butyl ester] 108 d 6-OMe NHCO G 1,1,3-Trioxo-1,2,3,4-tetrahydro-1l⁶-benzo[1,4]thiazin-6-yl 109 e 6-OMe NHCONH AY quinoxalin-2-yl cisstereochem 110 f 6-OMe NHCOO free base 3-oxo-3,4-dihydro-2H- transpyrido[3,2-b][1,4]thiazin-6-yl stereochem 111 g 6-OMe NHCOO free base3-oxo-3,4-dihydro-2H- cis benzo[1,4]thiazin-6-yl stereochem a Preparedfrom Example 102 by hydrogenation over palladium/carbon following theMethod of Example 36 b Prepared from Example 107 by reaction withtrifluoroacetic acid in dichloromethane c Prepared by alkylation ofExample (4c) with tert-butyl bromoacetate followed by reaction withamine (1c) and sodium triacetoxyborohydride by Method of Example 4 dPrepared from alcohol (4b) by oxidation with m-chloroperbenzoic acidfollowed by manganese dioxide and reaction of the carboxaldehyde withamine (1c) and sodium triacetoxyborohydride by Method of Example 4 ePrepared via cis-1-tert-butoxycarbonylamino-4-aminocyclohexane and6-methoxy[1,5]naphthyridine-4-isocyanate f Prepared from trans4-aminocyclohexanol by tert-butyloxycarbonyl protection of the aminogroup, followed by conversion of the hydroxy group to aminocarbonyloxyby reaction with phosgene followed by ammonia. The resultingtrans-(4-carbamoyloxy-cyclohexyl)-carbarnic acid tert butyl ester wasthen coupled with triflate (1b) according to the palladium-catalysedprocedure of (300d). Removal of the tert-butoxycarbonyl protecting group# and reductive alkylation with aldehyde (301d) using sodiumcyanoborohydride according to Example (311e) afforded the finalcompound. g Prepared from cis-4-aminocyclohexanol by the samemethodology as (f) above, except that aldehyde (4c) was used in place ofaldehyde (301d)

Example 150(R/S)-4-[(3-Oxo-3,4-dihydro-2H-benzo-[1,4]thiazin-6ylmethyl)-amino]-cyclohex-1-enecarboxylic acid (6-methoxy-[1,5]naphthyridin-4-yl)-amide oxalate

(a) (R/S)-4-tert-Butoxycarbonylamino-cyclohex-1-enecarboxylic acid

A solution of potassium hydroxide (25 g, 446 mmol) in water (30 mL) wasadded dropwise to a vigorously stirred solution of4-tert-butoxycarbonylaminocyclohexanone (13.53 g, 63.8 mmol) andbenzyltriethylammonium chloride (0.15 g, 0.64 mmol) in bromoform (25 mL)at 0° C. An exothermic reaction occurred, the internal temperaturereaching 80-90° C. before falling. Stirring, with external cooling, wascontinued for 1 hour. Water and dichloromethane were added and thephases were separated. The aqueous phase was washed withdichloromethane, then cooled in ice, acidified to pH 4 (dilutehydrochloric acid) and extracted with dichloromethane. The extracts weredried and evaporated to give the acid (7.78 g, 47%).

(b) (R/S)-4-tert-Butoxycarbonylamino-cyclohex-1-enecarboxylic acid(6-methoxy-[1,5]naphthyridin-4-yl)-amide

Method A. To a solution of the acid (150a) (2.58 g, 10 mmol) in drydichloromethane (20 mL) was added 1,1′-carbonyldiimidazole (2.26 g, 14mmol). The mixture was stirred for 7 hours at room temperature, thenevaporated. The residue was dissolved in dry DMF (20 mL),6-methoxy-[1,5]naphthyridin-4-ylamine (Example 1c) [RN 249889-69-8](2.49 g, 14 mmol) and N,N-dimethylaminopyridine (0.15 g) were added andthe mixture was heated at 100° C. for 48 hours. After evaporation ofsolvent, the residue was partitioned between ethyl acetate and water.The aqueous phase was re-extracted and the combined organics were washedwith water, dried and evaporated. Chromatography on silica gel (0-10%methanol/dichloromethane) gave an impure product which waschromatographed again (silica, 1-2% methanoldichloromethane) to give theamide (1.15 g. 29%).

Method B. To a solution of the acid (150a) (5.0 g, 20.8 mmol) in dry DMF(40 mL) were addedO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (7.98 g, 21 mmol) and triethylamine (5.88 mL, 42mmol). After 0.5 hours stirring at room temperature6-methoxy-[1,5]naphthyridin-4-ylamine (Example 1c) (3.64 g, 20.8 mmol)was added and the mixture was stirred at 50° C. for 48 hours. Work-up asfor Method A and chromatography on silica gel (1-3%methanol/dichloromethane) gave the amide (5.73 g, 69%).

MS (+ve ion electrospray) m/z 399 (MH+).

(c) (R/S)-4-Amino-cyclohex-1-enecarboxylic acid(6-methoxy-[1,5]-naphthyridin-4-yl)-amide

The amide (150b) (0.83 g, 2.1 mmol) was dissolved in dichloromethane (5mL) and trifluoroacetic acid (5 mL), and the solution was allowed tostand at room temperature for 2 hours, then evaporated. The residue wasdissolved in a small volume of aqueous sodium bicarbonate, basified topH10-11 with 40% sodium hydroxide and extracted thoroughly with 10%methanol/dichloromethane (total 125 mL). The extracts were dried andevaporated to give the amine (0.69 g, 100%).

MS (+ve ion electrospray) m/z 299 (MH+).

(d) Title Compound

A solution of the amine (150c) (0.10 g, 0.33 mmol) and3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxaldehyde (Example 4c)(0.064 g, 0.33 mmol) in dry chloroform (2 mL) and methanol (0.2 mL) washeated with 3 A molecular sieves for 15 hours. After cooling, sodiumtriacetoxyborohydride (0.35 g, 1.65 mmol) was added and the mixture wasstirred at room temperature overnight. The mixture was basified withaqueous sodium bicarbonate and the phases were separated. The aqueousphase was extracted with dichloromethane and the combined organics werewashed with water, dried and evaporated. Chromatography on silica gel(5-7% methanol/dichloromethane) gave the title compound as free base(0.08 g, 51%).

δH (d₆-DMSO, 400 MHz), 10.49 (1H, s), 9.88 (1H, s), 8.69 (1H, d), 8.43(1H, d), 8.28 (1H, d), 7.33 (1H, d), 7.24 (1H, d), 7.00-6.97 (2H, m),6.91 (1H, br s), 4.10 (3H, s), 3.72 (2H, s), 3.42 (2H, s), 2.74 (1H, m),2.67-2.37 (3H, m), 2.08 (1H, m), 1.98 (1H, m), 1.51 (1H, m). MS (+ve ionelectrospray) m/z 476(MH+).

The oxalate salt was prepared by the method of Example 1.

Example 151(R/S)-4-[(Benzo[1,2,5]thiadiazol-5-ylmethyl)-amino]-cyclohexenecarboxylic acid (6-methoxy-[1,5]naphthyridin-4-yl)-amide oxalate

(a) Benzo[1,2,5]thiadiazole-5-carboxaldehyde

This was prepared by oxidation of benzo[1,2,5]thiadiazol-5-yl-methanol(2a) with manganese dioxide in dichloromethane by the method of Example(4c).

(b) Title Compound

A solution of the amine (150c) (0,10 g, 0.3 mmol) and the carboxaldehyde(51a) (0.055 g, 0.33 mmol) in dry chloroform (2 mL) and methanol (0.2mL) was heated with 3A molecular sieves for 15 hours. After cooling,sodium triacetoxyborohydride (0.35 g, 1.65 mmol) was added and themixture was stirred at room temperature for 48 hours. The mixture wasbasified with aqueous sodium bicarbonate and extracted withdichloromethane. The extracts were dried and evaporated. Chromatographyon silica gel (2-5% methanol/dichloromethane)gave the title compound asthe free base (0.079 g, 53%).

δH (CDCl₃, 250 MHz), 9.37 (1H, s), 8.70 (1H, d), 8.55 (1H, d), 8.21 (1H,d), 7.92-8.03 (2H, m), 7.64 (1H, dd), 7.16 (1H, d), 6.94 (1H, br s),4.10 (3H, s), 4.08 (2H, s), 3.06-2.91 (1H, m), 2.80-2.39 (2H, m),2.32-2.07 (2H, m), 1.79-1.45 (3H, m). MS (+ve ion electrospray) m/z 447(MH⁺).

The oxalate salt was prepared by the method of Example 1.

Example 152(R/S)-4-[(Benzo[1,2,3]thiadiazol-5-ylmethyl)-amino]-cyclohex-1-enecarboxylic acid (6-methoxy-[1,5]naphthyridin-4-yl)amide oxalate

(a) Benzo[1,2,3]thiadiazole-5-carboxaldehyde

This was prepared by oxidation of benzo[1,2,3]thiadiazol-5-yl-methanol(6a) with manganese dioxide in dichloromethane by the method of Example(4c).

(b) Title Compound

This was prepared from the carboxaldehyde (152a) by the method ofExample 151 (0.75 g, 47%).

δH (CDCl₃, 250 MHz), 9.85 (1H, s), 8.69 (1H, d), 8.61 (1H, d), 8.54 (1H,d), 8.20 (1H, d), 8.05 (1H, d), 7.73 (1H, dd), 7.15 (1H, d), 6.94 (1H,br-s), 4.14 (2H, s), 4.09 (3H, s), 3.08-2.94 (1H, m), 2.80-2.43 (2H, m),2.33-2.08 (2H, m), 1.82-1.53 (3H, m). MS (+ve ion electrospray) m/z 447(MH+).

The oxalate salt was prepared by the method of Example 1.

Example 153(R/S)-4-[(2-Oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazin-7-ylmethyl)-amino]-cyclohex-1-enecarboxylic acid (6-methoxy-[1,5]naphthyridin-4-yl)-amide oxalate

A solution of the amine (150c) (0.10 g, 0.33 mmol) and2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine-7-carboxaldehyde(Example 13e) (0.064 g, 0.33 mmol) in dry chloroform (2 mL) and methanol(0.2 mL) was heated with 3A molecular sieves for 15 hours. Aftercooling, sodium triacetoxyborohydride (0.35 g, 1.65 mmol) was added andthe mixture was stirred at room temperature overnight. A further portionof sodium triacetoxyborohydride (0.16 g) was added and stirringcontinued overnight. The mixture was basified with aqueous sodiumbicarbonate and the phases were separated. The aqueous phase wasextracted with dichloromethane/methanol and the combined organics werewashed with brine, dried and evaporated. Chromatography on silica gel(2-5% methanol/dichloromethane) gave the title compound as the free base(0.055 g, 35%).

δH (CDCl₃/CD₃OD, 250 MHz), 9.93 (1H, s), 8.66 (1H, d), 8.55 (1H, d),8.21 (1H, d), 8.10 (1H, br s), 7.23-7.19 (2H, m), 6.94 (1H, br s), 4.12(3H, s), 3.84(2H, s), 3.55 (2H, s), 2.93 (1H, m), 2.80-2.45 (3H, m),2.16 (2H, m), 1.67 (1H, m). MS (+ve ion electrospray) m/z 477(MH+).

The oxalate salt was prepared by the method of Example 1.

Example 154(R/S)-4-[(7-Fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-amino]-cyclohex-1-enecarboxylic acid (6-methoxy-[1,5]naphthyridin-4-yl)-amide oxalate

This was prepared from the amine (150c) (0.10 g, 0.33 mmol) and7-fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxaldehyde(Example 9e) (0.065 g, 0.33 mmol) by the method of Example 153.Chromatography on silica gel (2-5% methanol/dichloromethane) gave thetitle compound as the free base (0.071 g, 39%).

δH (CDCl₃, 250 MHz), 9.86 (1H, s), 8.70 (1H, d), 8.55 (1H, d), 8.22 (1H,d), 7.16 (1H, d), 6.93 (1H, br s), 6.84 (1H, d), 6.72 (1H, d), 4.60 (2H,s), 4.10 (3H, s), 3.84(2H, s), 2.90 (1H, m), 2.78-2.43 (3H, m),2.24-2.00 (2H, m), 1.63 (m). MS (+ve ion electrospray) m/z 478(ME+).

The oxalate salt was prepared by the method of Example 1.

Example 155(R/S)-4-[(2-Oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylmethyl)-amino]-cyclohex-1-enecarboxylicAcid (6-methoxy-[1,5]naphthyridin-4-yl)-amide oxalate

(a) 6-Ethoxycarbonylmethoxy-5-nitro-nicotinic acid methyl ester

A solution of ethyl glyoxalate (2.80 g) in dry dioxan (100 mL), cooledin ice, was treated with sodium hydride (60% dispersion in oil; 1.30 g)and the mixture was heated at 50° C. for 30 minutes and cooled in ice. Asolution of 6-chloro-5-nitro-nicotinic acid methyl ester (5.25 g)[prepared as described by A. H. Berrie et al. J. Chem. Soc. 2590-2594(1951)] in dioxan (40 mL) was added and the solution was stirred at 0°C. for 30 minutes and then at room temperature overnight. The reactionmixture was evaporated to dryness, sodium bicarbonate solution was addedto pH 7, and the mixture extracted with chloroform, dried (anhydroussodium sulfate) and evaporated to afford a semi-solid that waschromatographed on silica gel [dichloromethane-hexane (1:1) thendichloromethane] to afford the product (4.70 g).

MS (+ve ion electrospray) m/z 285 (MH+).

(b) 2-Oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxylic acidmethyl ester

The ester (155a) (1.0 g) in acetic acid (80 mL) was treated with ironpowder (10 g) and the mixture was stirred and heated at 60° C. for 2.5hours, cooled and filtered. The filtrate was evaporated, treated withanhydrous sodium carbonate and extracted with warm chloroform-methanol(98:2). It was dried (anhydrous sodium sulfate) and evaporated to give awhite solid (5.2 g).

MS (+ve ion electrospray) m/z 209 (MH+).

(c) 2-Oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxylic Acid

The ester (155b) (4.5 g) was hydrolysed with aqueous sodium hydroxide intetrahydrofuran by the method of Example (4a) to afford a solid (3.0 g).

MS (−ve ion electrospray) m/z 193 (M−H⁻).

(d) 7-Hydroxymethyl-1H-pyrido[2,3-b][1,4]oxazin-2-one

The relatively insoluble carboxylic acid (155c) (1.20 g) was reactedwith isobutylchloroformate and sodium borohydride by the method ofExample (4b), except the initial solvent was tetrahydrofuran (350 mL),chloroform (50 mL) and dimethylformamide (10 mL). The reaction mixturewas evaporated to one quarter volume, extracted with dichloromethane,and the aqueous fraction evaporated to dryness, dissolved inmethanol-chloroform (1:3) and chromatographed on silica gel[methanol-dichloromethane (1:9)] to afford a solid (0.43 g).

MS (−ve ion electrospray) m/z 179 (M−H⁻).

(e) 2-Oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxaldehyde

The alcohol (155d) (0.42 g) in tetrahydrofuran (200 mL) and chloroform(100 mL) was oxidised with excess manganese dioxide by the method ofExample (4c) to afford the required product (0.30 g), containing 17% ofalcohol (55d) by NMR.

MS (−ve ion electrospray) m/z 177 (M−H⁻).

(f) Title Compound

This was prepared from the amine (150c) (0.132 g) and crudecarboxaldehyde (155e) (0.090 g) by the method of Example 153.Chromatography on silica gel (2-10% methanol/dichloromethane) gave thefree base of the title compound as a solid (0.090 g).

δH (CD₃OD, 250 MHz), 8.55 (1H, d), 8.50 (1H, d), 8.20 (1H, d), 7.86 (1H,d), 7.38 (1H, d), 7.28 (1H, d), 4.84 (2H, s), 4.17 (3H, s), 4.02 (2H,s), 2.93 (1H, m), 2.70 (1H, m) 2.25 (4H, m), 1.75 (2H, m) 1.45 (2H, m).MS (+ve ion electrospray) m/z 463(MH+).

The oxalate salt was prepared by the method of Example 1

Example 156(R/S)-4-[Carboxymethyl-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-ylmethyl)-amino]-cyclohex-1-enecarboxylicAcid (6-methoxy-[1,5]naphthyridin-4-yl)-amide Bis(trifluoroacetate) Salt

(a) (R/S)-4-(tert-Butoxycarbonylmethylamino)-cyclohex-1-enecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide

A solution of the amine (150c) (0.20 g, 0.66 mmol) in dry DMF (5 mL) wastreated with tert-butyl bromoacetate (0.107 mL, 0.66 mmol) and potassiumcarbonate and the mixture was stirred overnight at room temperature.After evaporation of solvent, the residue was chromatographed on silicagel (0-2% methanol/dichloromethane) to give the ester (0.093 g, 34%).

MS (+ve ion electrospray) m/z 413(MH+).

(b)(R/S)-4-[tert-Butoxycarbonylmethyl-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-ylmethyl)-amino]-cyclohex-1-enecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide

A solution of the ester (156a) (0.09 g, 0.2 mmol) and3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxaldehyde (Example 4c)(0.064 g, 0.33 mmol) in dry 1,2-dichloroethane (3 mL) was heated underreflux with 4A molecular sieves for 7.5 hours. After cooling to roomtemperature, sodium triacetoxyborohydride (0.175 g) was added and themixture was stirred overnight. More sodium triacetoxyborohydride (0.92g) and aldehyde (0.14 g) were added at intervals during which time themixture was heated under reflux overnight. Aqueous sodium bicarbonateand dichloromethane were added and the phases separated. The aqueousphase was re-extracted with dichloromethane and the combined organicswere washed with water, dried and evaporated. Chromatography on silicagel (2-5% methanol/dichloromethane) gave the alkylated product (0.012g), plus a 2:1 mixture of product and starting material (0.046 g).

MS (+ve ion electrospray) m/z 590(MH+).

(c) Title Compound.

The pure ester (156b) (0.012 g) was dissolved in dichloromethane (0.5mL) and trifluoroacetic acid (0.5 mL) and the solution was allowed tostand at room temperature for 2 hours. Evaporation to dryness gave thetitle compound (0.018 g).

δH (CD₃OD, 250 MHz) 8.88 (1H, d), 8.83 (1H, d), 8.38 (1H, d), 7.57 (1H,d), 7.43 (1H, d), 7.24 (1H, dd), 7.17 (1H, d), 7.04 (1H, br s), 4.49(2H, s), 4.23 (3H, s), 4.06 (2H, s), 3.78 (1H, m), 3.46 (2H, s),3.00-2.85 (2H, m), 2.85-2.55 (2H, m), 2.44 (1H, m), 1.95 (1H, m). MS(+ve ion electrospray) m/z 534(MH+).

The following Examples were prepared by analogous methods.

salt Method of G oxalate Example synthesis LINKER AY Dioxalate R 200 aNHCONH G (CH₂)₄Me 201 b NHCONH G (CH₂)₄Me trans stereochem. 202 a NHCONHAY quinoxalin-2-yl 203 d CONR AY quinoxalin-2-yl 204 c NHCO (CH₂)₅Me 205e CH(OH)CH₂NH G (CH₂)₄Me 206 f NHCOO free base

a Prepared via cis-1-tert-butoxycarbonylamino-4-aminocyclohexane and6-methoxyquinoline-4-isocyanate b Prepared fromfrans-1-tert-butoxycarbonylamino-4-aminocyclohexane and6-methoxyquinoline-4-isocyanate c Prepared from4-cis-tert-butoxycarbonylamino-cyclohexanecarboxylic acid and6-methoxyquinoline-4-ylamine by the Method of Example 1d d Prepared fromfrom cis-1-tert-butoxycarbonylamino-4-aminocyclohexane and6-methoxyquinoline-4-carboxylic acid by the method of Example 1d ePrepared from cis-1-tert-butoxycarbonylamino-4-aminocyclohexane byreaction with [R]-2-(6-methoxyquinolin-4-yl)oxirane f Prepared byanalogous procedures to those of Example 110

Unless otherwise stated, the following compounds were prepared byanalogous methods by reaction of an appropriate carboxaldehyde and aminewith sodium triacetoxyborohydride (Method of Example 153).

salt B Dihydrochloride Method of A Hydrochloride synthesis R Example(aldehyde) Stereochemistry Trihydrochloride R 210 (Example 301d) trans-cyclohexane B

211 a cyclohexene single enantiomer (slow) B

212 a cyclohexene single enantiomer (fast) B

213 b trans- cyclohexane B

214 c trans- cyclohexane B

215 d trans- cyclohexane B

216 e cis-cyclohexane B

a Prepared from Example 150b by preparative HPLC to give the singleenantiomers, which were converted to Examples 211 (from slow-runningenantiomer) & Example 212 (from fast-running enantiomer) by method ofExample 150c/d b 7-Fluoro-2,3-dihydro-benzo[1,4]dioxine-6-carboxaldehydeprepared from 6-fluoro-2,3-dihydro-benzo[1,4]dioxine [V. Daukas et alChemija, 1999, 10 (1), 59] by reaction of dichloromethyl methyl etherand titanium tetrachloride. c3,4-Dihydro-2H-benzo[1,4]thiazine-6-carboxaldehyde prepared from3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid methyl esterby reaction with lithium aluminium hydride followed by oxidation withmanganese dioxide. d Prepared from1-oxo-1,2-dihydro-isoquinoline-3-carboxaldehyde [AR. Modi et at IndianJ. Chem. 17b 624-6 (1979)] e Prepared fromcis-4-amino-cyclohexanecarboxylic acid(6-methoxy-[1,5]naphthyridine-4-yl)-amide (itself derived fromcis-cyclohexane-1,4-dicarboxylic acid mono-tert-butyl ester using thepalladium-catalysed chemistry of Example 300d) by analogous methods tothe trans-series (Example 1f)

Example 3001-Hydroxy-t-4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-ylmethyl)-amino]-r-cyclohexanecarboxylicAcid (6-methoxy-[1,5]naphthyridin-4-yl)-amide Dihydrochloride

(a) trans/cis-(4-Cyano-4-hydroxy-cyclohexyl)-carbamic acid tert butylester

(4-Oxo-cyclohexyl)-carbamic acid tert-butyl ester (50 g, 230 mmol) wasadded to a vigorously stirred mixture of ethyl acetate (1 liter) andwater (750 ml) containing sodium hydrogen carbonate (40 g) and potassiumcyanide (23 g, 352 mmol). After 20 hours, the phases were separated andthe organic extract washed with water then brine. The ethyl acetatephase was dried (MgSO4) then evaporated to give a pale yellow foam (55.2g, 100%) which was used without further purification.

MS (+ve ion electrospray) m/z 241 (MH+).

(b) trans/cis-4-Amino-1-hydroxy-cyclohexanecarboxylic acid amidehydrochloride

The cyanohydrins (300a) (27.6 g, 115 mmol) were dissolved inconcentrated hydrochloric acid (300 ml) (caution—mildly exothermic onthis scale, and evolution of CO2). After 2 hours the mixture wasevaporated to dryness, azeotroping with toluene then chloroform (ca 3times each). The material was used crude.

MS (+ve ion electrospray) m/z 159 (MH+).

(c) (4-Carbamoyl-r-4-hydroxy-c-cyclohexyl)-carbamic acid tert butylester (Method A)

The amine (300b) (approximately 115 mmol) was dissolved in 2M aqueoussodium hydroxide (200 ml) then treated with a solution of di-tert-butyldicarbonate (26.7 g, 123 mmol) in dioxan (125 ml). The mixture wasstirred for 2 hours then filtered. The filtrate was partitioned betweenethyl acetate (ca 1.5 liters) and brine (ca 1 liter). The organicextract was washed with brine, dried, and evaporated to give a whitesolid (ca 6.5 g) which was approximately a 1:1 mixture of trans/cis.Chromatography on silica gel, eluting with a 0-10% methanol indichloromethane gradient, afforded the single carbamate as a white solid(2.5 g) (slower running isomer).

MS (+ve ion electrospray) m/z 259 (MH+).

(d)[r-4-Hydroxy-4-(6-methoxy-[1,5]naphthyridin-4-ylcarbamoyl)-c-cyclohexyl]-carbamicacid tert-butyl ester

A mixture of the amide (300c) (0.51 g), cesium carbonate (0.818 g),tris(dibenzylideneacetone)dipalladium(0) (38 mg), andrac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (77.4 mg) in dry dioxan(20 ml) under argon, was sonicated for 10 minutes.1,1,1-trifluoro-methanesulfonic acid 6-methoxy-[1,5]naphthyridin-4-ylester (1b) (0.64 g) was added, and the mixture was stirred and heated at85° C. for 18 hours, under argon. The mixture was cooled, filtered, andthe filtrate evaporated and chromatographed on silica gel, eluting withchloroform, then (1-2%) methanol-dichloromethane, to afford a solid(0.85 g).

MS (+ve ion electrospray) m/z 417 (MH+).

(e) t-4-Amino-1-hydroxy-r-cyclohexanecarboxylic acid(6-hydroxy-[1,5]naphthyridin-4-yl)-amide

The carbamate (300d) (0.85 g) in dichloromethane (30 ml) was treatedwith trifluoroacetic acid (30 ml) for 2 hours and evaporated. Water andsodium carbonate solution were added and the resulting solid wascollected, washed with water and dried in vacuo, to afford a white solid(0.64 g).

MS (+ve ion electrospray) m/z 317 (MH+).

(f) Title Compound

A mixture of carboxaldehyde (4c) (69 mg) and amine (300e) (95 mg) inchloroform (4 ml) and methanol (4 ml) with 3A molecular sieves washeated under reflux for 3 hours, cooled, and treated with sodiumtriacetoxyborohydride (191 mg). After stirring at room temperature for 4days, the mixture was diluted with chloroform (20 ml) and washed withaqueous sodium carbonate. The aqueous was re-extracted with chloroformand the combined organic fractions dried (Na₂SO₄) and evaporated andchromatographed on silica gel, eluting with 2-10%methanol-dichloromethane to give free base of the title compound (80mg).

¹H NMR δ(CDCl₃/CD₃OD) 1.5-1.7 (2H, m), 1.8-2.0 (4H, m), 2.0-2.2 (2H, m),2.72 ((1H, m), 3.45 (2H, s), 3.85 (2H, s), 4.17 (3H, s), 6.92 (1H, d),7.02 (1H, dd), 7.24 (1H, d), 7.32 (1H, d), 8.20 (1H, d), 8.57 (1H, d),8.65 (1H, d) MS (+ve ion electrospray) m/z 494 (MH⁺)

The free base, in chloroform/methanol (1:1) was treated with 4M HCl indioxan (0.5 ml) and evaporated to dryness. The solid was triturated withether, filtered and dried in vacuo, to provide title compound (85 mg).

Alternative preparation of Example (300c)(4-Carbamoyl-r-4-hydroxy-c-cyclohexyl)-carbamic acid tert-butyl ester(Method B)

(g) 2-Acetoxycyclohex-3-enecarboxylic Acid Butyl ester

1-Acetoxy-1,3-butadiene (30.1 g, 0.268 mol) was dissolved in toluene (20mL). To this was added butyl acrylate (37.9 mL, 0.265 mol) andhydroquinone (0.14 g). The colourless solution was heated at 120° C. for26 h under argon. More 1-acetoxy-1,3-butadiene (10.6 g, 0.095 mol) intoluene (2 mL) was then added, and heating continued for a further 68 h.The solution was cooled then evaporated in vacuo to give a viscousyellow oil (69 g), which was used without further purification.

δH (CDCl₃) 0.91-0.95 (3H, m), 1.3-2.2 (1H, m), 2.6-2.72 (1H, m),4.01-4.16 (2H, m), and 5.48-6.07 (3H, m).

(h) Cyclohexa-1,3-dienecarboxylic Acid Butyl ester

Crude butyl ester (300 g) (55.25 g, max 0.207 mol) was dissolved in drytetrahydrofuran (320 mL) and cooled in an ice/salt bath. To this wasadded slowly, over 1 h, potassium t-butoxide in tetrahydrofuran (1 M,220 mL, 0.22 mol). After 0.5 h water and petroleum ether were added andthe mixture filtered quickly through kieselguhr. The phases wereseparated and the aqueous extracted with more petroleum ether (×2). Thecombined organic extracts were washed with brine, dried and evaporatedto give a mobile orange oil (31.85 g, 86%), which was used immediatelywithout further purification.

δH (CDCl₃) 0.93-0.99 (3H, m), 1.3-1.7 (4H, m), 2.2-2.5 (4H, m), 4.1-4.2(2H, m), 6.0-6.2 (2H, m), and 6.95-7.02 (1H, m).

(i) 2-Oxa-3-aza-bicyclo[2.2.2]oct-5-ene-1,3-dicarboxylic acid 3-benzylEster 1-butyl Ester

Crude butyl ester(300h) (31.84 g, max 0.176 mol) was dissolved indichloromethane (300 mL). To this was added N-hydroxy carbamic acidbenzyl ester (30.9 g, 0.185 mol). This solution was cooled in anice/salt bath then a solution of tetrabutylammonium periodate (80.1 g,0.185 mol) in dichloromethane (100 mL) was added dropwise over 1 h.After stirring for a further 1 h, with cooling, the mixture was reducedto a small volume in vacuo then stirred vigorously while adding diethylether (1 L). The mixture was filtered washing well with diethyl ether.The filtrate was then washed with aqueous sodium bisulphite (×2), andbrine, dried and evaporated to give a brown oil. This residue waspurified by chromatography on silica gel, eluting with 25-28% diethylether in petroleum ether, to give a viscous pale orange oil (42.41 g,˜69%) (contaminated with a little benzyl alcohol).

δH(CDCl3) 0.94 (3H, t), 1.35-1.75 (6H, m)₇ 2,15-2.4 (2H, m), 4.2-4.35(2H, m), 4.84-4.89 (1H, m), 5.12-5.20 (2H, m), 6.59-6.71 (2H, m), and7.28-7.39 (5H, m).

(j) 2-Oxa-3-aza-bicyclo[2.2.2]oct-5-ene-1,3-dicarboxylic Acid 3-benzylEster

To a solution of di-ester (300i) (42.13 g, 0.122 mol) in 1,4-dioxane(250 mL) was added aqueous sodium hydroxide solution (0.5 M, 250 mL,0.125 mol). The mixture was stirred for 50 min then washed with diethylether (×3). The aqueous phase was adjusted to pH2 with 5 M hydrochloricacid, and extracted with ethyl acetate (×3). The combined organicextracts were washed with brine, dried and evaporated to give a creamsolid (29.53 g, 84%).

δH (CDCl₃/CD₃OD) 1.53-1.79 (2H, m), 2.13-2.39 (2H, m), 4.82-4.89 (1H,m), 5.11-5.23 (2H, m), 6.57-6.69 (2H, m), and 7.3-7.4 (5H, m).

(k) 1-Carbamoyl-2-oxo-3-aza-bicyclo[2.2.2]oct-5-ene-3-carboxylic acidbenzyl ester

The benzyl ester (300j) (12.0 g, 41.5 mmol) and1-hydroxy-7-azabenzotriazole (6.26 g, 46 mmol) were dissolved in DMF(100 mL) then 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (8.79 g, 46 mmol) added. After stirring for 5 min ammoniumhydrogen carbonate (8.22 g, 104 mmol) was added. Four further smallportions of ammonium hydrogen carbonate were added over the next 7 h.The mixture was then stirred overnight, diluted with water and extractedwith ethyl acetate (×4). The combined organic extracts were washed with5% aqueous citric acid then brine, dried and evaporated to give anoff-white solid (9.9 g, 83%).

MS (+ve ion electrospray) m/z 289 (MH+).

(c) (4-Carbamoyl-r-4-hydroxy-c-cyclohexyl)-carbamic acid tert butylester

The benzyl ester (300 k) (9.75 g, 33.8 mmol) was dissolved in1,4-dioxane (150 mL) and water (60 mL) and hydrogenated over 10%palladium on carbon (50% aqueous paste, 3.3 g) at 40° C. and 55 psi for68 h. More catalyst (2 g) was added after 4 h. The mixture was thenfiltered through kieselguhr, washing well with 1,4-dioxane and water. Tothis solution was added 2 N sodium hydroxide (25 mL, 50 mmol) followedby a solution of di-tert-butyl dicarbonate (11.12 g, 51 mmol) in1,4-dioxane (10 mL). The reaction mixture was stirred for 5 h thenreduced in volume in vacuo, before extracting with ethyl acetate (×5).The combined organic extracts were dried and evaporated to give a whitesolid (5.96 g), which was chromatographed on silica (400 g). Elutionwith 0-6.5% methanol in dichloromethane gave a white powder (5.52 g,63%), identical to the material produced earlier.

δH (d₆-DMSO) 1.3-1.76 (17H, m), 3.17 (1H, br s), 4.95 (1H, s), 6.71 (1H,d), 7.0 (1H, s), and 7.14 (1H, s).

Alternative Preparation of1-carbamoyl-2-oxa-3-aza-bicyclo[2.2.2]oct-5-ene-3-carboxylic acid benzylester (300 k)

(1) Acetic acid 6-carbamoyl-cyclohex-2-enyl ester

1-Acetoxy-1,3-butadiene (20.79 g, 0.185 mol) was dissolved in toluene(21 mL). To this was added acrylamide (11.98 g, 0.168 mol) andhydroquinone (0.111 g). The colourless solution was heated at 110° C.for 116 h under argon. More 1-acetoxy-1,3-butadiene (5.67 g, 0.051 mol)was then added, and heating continued for a further 24 h. The solutionwas cooled then dichloromethane added. This solution was purified byBiotage 75 chromatography twice on silica (2×400 g) to give the titlecompound as a viscous oil (21.76 g, 71%), which solidified on standing;

δH (CDCl₃) 1.85-2.7 (8H, m), and 5.5-6.08 (5H, m).

(m) Cyclohexa-1,3-dienecarboxylic acid Amide

The ester (300 l) (16.28 g, 89 mmol) was dissolved in drytetrahydrofuran (200 mL) and cooled in an ice bath. To this was addedslowly, over 0.5 h, potassium t-butoxide in tetrahydrofuran (1 M, 100mL, 100 mmol). After stirring for 0.5 h with cooling and 2.5 h at roomtemperature, ethyl acetate was added and the solution washed with alittle water. The organic phase was dried and evaporated to give a brownoil (>100%). This was used immediately without further purification.

(k) 1-Carbamoyl-2-oxa-3-aza-bicyclo[2.2.2]oct-5-ene-3-carboxylic acidbenzyl ester

Crude amide (300 m) (max 89 mmol) was dissolved in dichloromethane (150mL). To this was added N-hydroxy carbamic acid benzyl ester (15.61 g,93.5 mmol). This solution was cooled in an ice bath then a solution oftetrabutylammonium periodate (40.49 g, 93.5 mmol) in dichloromethane (50mL) was added dropwise over 0.5 h. After stirring for a further 14 h themixture was reduced to a small volume in vacuo then diluted with ethylacetate(500 mL). The mixture was then washed with water, aqueous sodiumbisulphite (×3), and brine, dried and evaporated to give a yellow solid.This residue was purified by Biotage 75 chromatography on silica (800g), eluting with 22-60% ethyl acetate in petroleum ether, to give awhite solid (9.47 g, 37%);

δH (CDCl₃) 1.52-1.62 (1H, m), 1.75-1.86 (1H, m), 2.12-2.24 (2H, m), 4.81-4.88 (1H, m), 5.11-5.23 (2H, m), 5.6 (1H, br s), 6.51-6.64 (3H, m), and7.3-7.4 (5H, m).

Example 3011-Hydroxy-t-4-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)-amino]-r-cyclohexanecarboxylicAcid (6-methoxy-[1,5]naphthyridin-4-yl)-amide Dihydrochloride

(a) Methyl 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylate

A solution of ethyl 2-mercaptoacetate (1.473 ml) in DMF (48 ml) wasice-cooled and treated with sodium hydride (540 mg of a 60% dispersionin oil). After 1 hour methyl 6-amino-5-bromopyridine-2-carboxylate (3 g)(T. R. Kelly and F. Lang, J. Org. Chem. 61, 1996, 4623-4633) was addedand the mixture stirred for 16 hours at room temperature. The solutionwas diluted with EtOAc (1 liter), washed with water (3×300 ml), driedand evaporated to about 10 ml. The white solid was filtered off andwashed with a little EtOAc to the ester (0.95 g).

MS (APCI⁻) m/z 223 ([M−H]⁻, 100%)

(b) 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic acid

A solution of ester (301a) (788 mg) in dioxan (120 ml)/water (30 ml) wastreated dropwise over 2 hours with 0.5M NaOH solution (8 ml) and stirredovernight. After evaporation to approx. 3 ml, water (5 ml) was added and2N HCl to pH4. The precipitated solid was filtered off, washed with asmall volume of water and dried under vacuum to give a solid (636 mg).

MS (APCI⁻) m/z 209 (M−H]⁻, 5%), 165([M-COOH]⁻, 100%)

(c) 6-Hydroxymethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine

A solution of the carboxylic acid (301b) (500 mg) in TIF (24 ml) withtriethylamine (0.396 ml) was cooled to −10° C. and isobutylchloroformate (0.339 ml) added. After 20 minutes the suspension wasfiltered through kieselguhr into an ice-cooled solution of sodiumborohydride (272 mg) in water (8 ml), the mixture stirred 30 minutes andthe pH reduced to 7 with dilute HCl. The solvent was evaporated and theresidue triturated under water. The product was filtered and dried undervacuum to give a white solid (346 mg).

MS (APCI⁻) m/z 195 ([M−H]⁻, 50%), 165(100%)

(d) 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxaldehyde

A solution of the alcohol (301c) (330 mg) in dichloromethane (30 ml)/TBF(30 ml) was treated with manganese dioxide (730 mg) and stirred at roomtemperature. Further manganese dioxide was added after 1 hour (730 mg)and 16 hours (300 mg). After a total of 20 hours the mixture wasfiltered through kieselguhr and the filtrate evaporated. The product wastriturated with EtOAc/hexane (1:1) and collected to give a solid (180mg).

MS (APCI⁻) m/z 195 ([M−H]⁻, 95%), 165 (100%)

(e) Title compound

A mixture of the carboxaldehyde (301d) (62 mg) and amine (300e) (100 mg)in chloroform (1.5 ml)/methanol (1.5 ml) with 3A molecular sieves wasrefluxed 8 hours, cooled and treated with sodium triacetoxyborohydride(237 mg). After stirring overnight, the mixture was diluted withchloroform (20 ml) and washed with aqueous NaHCO₃. The aqueous wasre-extracted with chloroform and the combined organic fractions driedover MgSO₄ and evaporated. Chromatography of the residue(CHCl₃/MeOH/NH₄OH 95:5:0.5) gave free base of the title compound (100mg).

¹HNMR δ(CDCl₃/CD₃OD) 1.5-1.7 (2H, m), 1.8-2.0 (4H, m), 2.0-2.2 (2H, m),2.6-2.7 (1H, m), 3.50 (2H, s), 3.87 (2H, s), 4.17 (3H, s), 6.98 (1H, d),7.24 (1H, d), 7.67 (1H, d), 8.18 (1H, d), 8.53 (1H, d), 8.63 (1H, d)

This material as a solution in chloroform/methanol 1:1 was treated with1M HCl in ether (0.5 ml) and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thetitle compound (112 mg).

MS (+ve ion electrospray) m/z 495 (MH⁺, 100%)

Example 3021-Hydroxy-t-4-[(2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]thiazin-7-ylmethyl)-amino]-r-cyclohexanecarboxylicAcid (6-methoxy-[1,5]naphthyridin-4-yl)-amide Dihydrochloride

(a) 5-Fluoro-2-picoline N-oxide

The preparation was based on E. J. Blanz, F. A. French, J. R. DoAmaraland D. A. French, J. Med. Chem. 13, 1970, 1124-1130. 5-Amino-2-picoline(12.5 g) in ethanol (105 ml) and 50% fluoroboric acid (44.5 ml) wasstirred at −5° C. and treated dropwise over 45 minutes. with n-butylnitrite (31.25 ml). The solution was maintained at this temp. for 3hours, treated with ether (100 ml, precooled to −20° C.) and the solidfiltered off, quickly transferred to a flask and covered with hexane(precooled to −20° C.). After allowing to warm to approx. 20° C. andstanding for 3 days the hexane was decanted and 2M NaOH solution addeduntil basic (pH 10). The mixture was filtered and the filtrate extractedwith dichloromethane (10×200 ml). The organic solution was dried,evaporated to 200 ml and treated with m-chloroperbenzoic acid (26.5 g).After stirring 16 hours the solution was washed with excess aqueoussodium bicarbonate and the aqueous re-extracted with dichloromethane(10×200 ml). The organic fraction was dried and evaporated and theresidue chromatographed (15% EtOH/EtOAc) to give the pyridine N-oxide(5.5 g).

MS (APCI⁺) m/z 128 (MH⁺, 100%)

(b) 5-Fluoro-4-nitro-2-picoline N-oxide

The pyridine N-oxide (302a) (2.12 g) was treated with an ice-cooledmixture of fuming nitric acid (7.1 ml) and conc. sulfuric acid (7.1 ml),heated at 35-40° C. for 1 hour and 65-70° C. for 5.5 hours, cooled andice (45 g) added. 10M NaOH was added to pH 10 and the mixture extractedwith EtOAc (3×30 ml). The organic fraction was dried and evaporated togive a yellow solid (2.16 g).

MS (APCI⁺) m/z 173 (MH⁺, 30%), 127 (100%)

(c) 5-Ethoxycarbonylmethylthio-4-nitro-2-picoline N-oxide

Ethyl 2-mercaptoacetate (1.51 g) in dioxan (15.6 ml) under argon wastreated with sodium hydride (550 mg of a 60% dispersion in oil) andstirred for 4 hours. The pyridine N-oxide (302b) (2.16 g) was added andstirring was continued for 3 days. Water (50 ml) was added and themixture extracted with chloroform (3×50 ml). The organic fraction wasdried and evaporated to give a yellow solid (3.31 g).

MS (APCI⁺) m/z 273 (MH⁺, 80%), 125 (100%)

(d) 2-Acetoxymethyl-5-ethoxycarbonylmethylthio-4-nitropyridine

A solution of the ester (302c) (3.31 g) in acetic anhydride (43 ml) washeated to 80° C. for 6 hours, evaporated, xylene (100 ml) added andevaporated. Chromatography of the residue (eluent EtOAc/hexane 1:1) gavethe pyridine (1.03 g).

(e) 7-Acetoxymethyl-2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]thiazine

A solution of the pyridine (302d) (1.03 g) in glacial acetic acid (27.5ml) was treated with iron powder (1.75 g), stirred at 60° C. for 3hours, filtered through kieselguhr and evaporated to dryness. Saturatedaqueous sodium bicarbonate (300 ml) was added and the mixture extractedwith EtOAc (3×200 ml). The organic fraction was dried and evaporated.The residue was redissolved in acetic acid (30 ml), heated to 100° C.for 24 hours, evaporated and chromatographed (eluent EtOAc/hexane 1:1)to give a solid (340 mg).

MS (APCI⁻) m/z 237 ([M−H]⁻, 90%), 195 (100%)

(f) 7-Hydroxymethyl-2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]thiazine

A solution of the pyridothiazinone (302e) (340 mg) in dioxan (9 ml) wastreated dropwise over 2 hours with 0.5M NaOH (3.7 ml), stirred for 18hours and evaporated. Water (10 ml) was added and the product filteredoff, washed with water and dried under vacuum to give a white solid (231mg).

MS (APCI⁻) m/z 195 ([M−H]⁻, 100%)

(g) 2-Oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]thiazine-7-carboxaldehyde

A mixture of the pyridothiazinone (226 mg) manganese dioxide (600 mg),THF (22.5 ml) and 1,2-dichloroethane (22.5 ml) was heated at 65° C. for18 hours under argon. Filtration through kieselguhr and evaporation ofsolvent gave the product as an off-white solid (173 mg).

MS (APCI⁻) m/z 193 ([M−H]⁻, 100%)

(h) Title Compound

A mixture of the carboxaldehyde (302 g) (62 mg) and amine (300e) (100mg) in chloroform (1.5 ml)/methanol (1.5 ml) with 3A molecular sieveswas refluxed for 24 hours, cooled and treated with sodiumtriacetoxyborohydride (237 mg). After stifling overnight, the mixturewas diluted with chloroform (20 ml) and washed with aqueous NaHCO₃. Theaqueous fraction was re-extracted 3 times with 20% ethanol in chloroformand the combined organic fraction dried over MgSO₄ and evaporated.Chromatography of the residue (CHCl₃/MeOH/NH₄OH 95:5:0.5) gave free baseof the title compound (88 mg).

¹H NMR δ(CDCl₃/CD₃OD) 1.5-1.7 (2H, m), 1.8-2.2 (6H, m), 2.5-2.7 (1H, m),3.48 (2H, s), 3.87 (2H, s), 4.17 (3H, s), 6.91 (1H, s), 7.22 (1H, d),8.17 (1H, d), 8.37 (1H, s), 8.54 (1H, d), 8.62 (1H, d)

This material as a solution in chloroform/methanol 1:1 was treated with1M HCl in ether (0.5 ml) and evaporated to dryness. The solid was driedunder vacuum to provide the title compound (78 mg).

MS (+ve ion electrospray) m/z 495 (MH⁺, 100%)

Example 3031-Hydroxy-t-4-[(2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazin-7-ylmethyl)-amino]-r-cyclohexanecarboxylicAcid (6-methoxy-[1,5]naphthyridin-4-yl)-amide Dihydrochloride

(a) Title Compound

A mixture of the carboxaldehyde (13e) (37 mg) and amine (300e) (55 mg)in chloroform (4 ml)/methanol (4 ml) with 3A molecular sieves wasrefluxed for 3 hours, cooled and treated with sodiumtriacetoxyborohydride (300 mg), portionwise. After stirring at roomtemperature for 7 days, the mixture was diluted with chloroform andwashed with aqueous Na₂CO₃ solution, dried over Na₂SO₄ and evaporatedThe residue was chromatographed on silica gel, eluting with 2-10%methanol-dichloromethane to give the free base of the title compound (30mg).

¹H NMR δ(CDCl₃/CD₃OD) 1.5-1.7 (2H, m), 1.8-2.2 (6H, m), 2.65 (1H, m)3.60 (2H, s), 3.81 (2H, s), 4.17 (3H, s), 6.91 (1H, s), 7.21 (1H, d),7.25 (1H, d), 8.10 (1H, d), 8.18 (1H, d), 8.55 (1H, d), 8.62 (1H, d)

This material as a solution in chloroform/methanol 1:1 was treated with4M HCl in dioxan (0.2 ml) and evaporated to dryness. The solid was driedin vacuo to provide the title compound (35 mg).

MS (+ve ion electrospray) m/z 495 (MH⁺, 100%)

Example 3041-Hydroxy-t-4-[(7-bromo-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)-amino]-r-cyclohexanecarboxylicAcid (6-methoxy-[1,5]naphthyridin-4-yl)-amide Dihydrochloride

(a) Methyl 6-amino-3,5-dibromopyridine-2-carboxylate

A solution of methyl 6-amino-3-bromopyridine-2-carboxylate (20.62 g) (T.R. Kelly and F. Lang, J. Org. Chem. 61, 1996, 4623-4633) in chloroform(570 ml) was treated dropwise over 2 hours with bromine (4.62 ml) inchloroform (115 ml) and stirred 16 hours. The solution was washed withexcess aqueous sodium bicarbonate, dried and evaporated. Crystallisationfrom EtOAc/hexane gave the bromopyridine (13.5 g).

MS (APCI⁺) m/z 309, 311, 313 (MH⁺, 70%), 295, 297, 299 (100%).

(b) Methyl7-bromo-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylate

This was prepared from methyl 6-amino-3,5-dibromopyridine-2-carboxylate(12.75 g) by the method of Example (301a) to give 5.85 g.

MS (APCI⁺) m/z 303, 305 (MH⁺, 30%), 271, 273 (100%)

(c) 7-Bromo-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylicAcid

This compound was prepared (73%) from the ester (304b) by the method ofExample (301b)

MS (APCI⁻) m/z 287,289 ([M−H]⁻, 3%), 243, 245 ([M—COOH]⁻, 100%)

(d)7-Bromo-6-hydroxymethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine

This compound was prepared (80%) from carboxylic acid (304c) by themethod of Example (301c).

MS (APCI⁺) m/z 275, 277 (MH^(+,) 20%), 257,259 (100%)

(e)7-Bromo-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxaldehyde

A mixture of the 7-bromo-pyridothiazinone (304d) (518 mg), manganesedioxide (870 mg), THF (45 ml) and 1,2-dichloroethane (45 ml) was heatedat 60° C. under argon. Further manganese dioxide was added after 4 hours(870 mg) and 20 hours (600 mg).

After a total of 30 hours filtration through kieselguhr and evaporationof solvent gave a solid (320 mg).

MS (APCI⁻) m/z 271, 273 ([M−H]⁻, 40%), 152 (100%)

(f) Title Compound

A mixture of the carboxaldehyde (304e) (87 mg) and the amine (300e) (100mg) in chloroform (2 ml)/methanol (2 ml) with 3A molecular sieves wasrefluxed 18 hours, cooled and treated with sodium triacetoxyborohydride(237 mg). After stirring overnight, the mixture was diluted withchloroform (20 ml) and washed with aqueous NaHCO₃. The aqueous fractionwas re-extracted with 20% ethanol in chloroform and the combined organicfractions dried (MgSO₄) and evaporated. Chromatography of the residue(CHCl₃MeOH/NH₄OH 95:5:0.5) gave free base of the title compound (80 mg).

¹H NMR δ(CDCl₃/CD₃OD) 1.5-1.7 (2H, m), 1.8-2.2 (6H, m), 2.6-2.8 (1H, m),3.51 (2H, s), 3.99 (2H, s), 4.17 (3H, s), 7.22 (1H, d), 7.85 (1H, s),8.18 (1H, d), 8.54 (1H, d), 8.63 (1H, d)

This material as a solution in chloroform/methanol 1:1 was treated with1M HCl in ether (0.35 ml) and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thetitle compound (90 mg).

MS (+ve ion electrospray) m/z 573 and 575 (MH⁺, 100%)

Example 3051-Hydroxy-t-4-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylmethyl)-amino]-r-cyclohexanecarboxylicAcid (6-methoxy-[1,5]naphthyridin-4-yl)-amide Dihydrochloride

(a) 2-Bromo-5-hydroxy-6-nitropyridine

3-Hydroxy-2-nitropyridine (20 g, 0.143 mole) was dissolved in methanol(400 ml) and a solution of 25% sodium methoxide in methanol (33 ml, 0.13mole) was added at room temperature. The mixture was stirred for 30 min,then was cooled to 0° C., and bromine (7.2 ml, 0.14 mole) was addedslowly. The reaction was then stirred at 0° C. for 30 min, then wasquenched with glacial AcOH (2.5 ml). The solvent was removed in vacuo toafford material (30 g, 96%), which was used without furtherpurification.

MS (ES) m/z 219.0 (M+H)⁺.

(b) Ethyl (6-bromo-2-nitro-pyridin-3-yloxy)acetate

The hydroxypyridine (305a) (30 g, 0.14 mole) was suspended in acetone(200 ml), and potassium carbonate (39 g, 0.28 mole) was added, followedby ethyl bromoacetate (15.7 ml, 0.14 mmole). The reaction was heated atreflux for 10 hr, then was cooled to room temperature and diluted withEt₂O. The precipitate was removed by suction filtration, and thefiltrate was concentrated in vacuo to afford material (38 g, 89%), whichwas used without further purification.

MS (ES) m/z 305.0 M+H)⁺.

(c) 6-Bromo-4H-pyrido[3,2-b][1,4]oxazin-3-one

The nitropyridine (305b) (38 g, 0.125 mole) was dissolved in glacialAcOH (150 ml), and iron powder (20 g, 0.36 mole) was added. The mixturewas mechanically stirred and heated at 90° C. for 5 hr, then was cooledto room temperature and diluted with EtOAc (300 ml). The mixture wasfiltered through a pad of silica gel and the filtrate was concentratedin vacuo and the residue recrystallized from MeOH (15 g, 52%).

MS (ES) m/z 229.0 (M+H)⁺.

(d) 6-((E)-Styryl)-4H-pyrido[3,2-b][1,4]oxazin-3-one

The bromopyridine (305c) (6.0 g, 26.3 mmole) andtrans-2-phenylvinylboronic acid (3.9 g, 26.3 mmole) were dissolved in1,4-dioxane (150 ml) and the solution was degassed with argon. (Ph₃P)₄Pd(230 mg, 0.2 mmole) was added, followed by a solution of potassiumcarbonate (6.9 g, 50 mmole) in H₂O (20 ml). The reaction was heated atreflux under argon overnight, then was cooled to room temperature anddiluted with EtOAc (200 ml). The solution was washed sequentially withH₂O and brine, dried (Na₂SO₄), and concentrated in vacuo. The solidresidue was purified by flash chromatography on silica gel (5-10%EtOAc/CHCl₃) to afford a solid (2.5 g, 38%).

MS (ES) m/z 253.0 M+H)⁺.

(e) 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxaldehyde

The pyridine (305d) (1.2 g, 4.8 mmole) was dissolved in CH₂Cl₂ (200 ml)and the solution was cooled to −78° C. Ozone was bubbled through thesolution with stirring until a pale blue color appeared, then the excessozone was removed by bubbling oxygen through the solution for 15 min.Dimethylsulfide (1.76 ml, 24 mmole) was added to the solution, and thereaction was stirred at −78° C. for 3 hr, then at room temperatureovernight. The solvent was removed in vacuo, and the residue wastriturated with Et₂O (50 ml). The collected solid was washed withadditional Et₂O and dried to afford a solid (700 mg, 82%).

MS (ES) m/z 179.0 (M+H)⁺.

(e) Title Compound

A mixture of the carboxaldehyde (305e) (0.5 g; 2.8 mmol) and amine(300e) (0.93 g; 2.94 mmol) in methanol (35 ml)/dimethylformamide (35ml)/acetic acid (3.5 ml) was heated at 80° C. with 3A molecular sievesfor 3 hours, cooled and treated with sodium cyanoborohydride (0.6 g; 9.5mmol). After stirring overnight at room temperature, the mixture wasdiluted with methanol-chloroform (1:1), filtered and the filtrateevaporated to dryness. It was treated with aqueous sodium carbonate andextracted (4×) with methanol-chloroform (1:9), dried (sodium sulfate),and evaporated to dryness. Chromatography of the residue (2-10%methanol-dichloromethane) gave free base of the title compound (1.03 g;74%).

¹H NMR δ(CDCl₃/CD₃OD) 1.5-1.7 (2H, m), 1.8-2.0 (4H, m), 2.0-2.12 (2H,m), 2.6-2.7 (1H, m), 3.38 (2H, s), 3.83 (2H, s), 4.17 (3H, s), 6.96 (1H,d), 7.25 (2H, m), 8.18 (1H, d), 8.53 (1H, d), 8.62 (1H, d).

This material as a solution in chloroform/methanol 1:1 was treated withexcess 4M HCl in dioxan and evaporated to dryness. The solid wastriturated with ether, filtered and dried in vacuo to give the titlecompound, as a white solid.

MS (+ve ion electrospray) m/z 479 (MH⁺)

Example 3061-Hydroxy-t-4-[(7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)-amino]-r-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide Dihydrochloride

(a) Methyl 6-amino-5-bromo-3-chloropyridine-2-carboxylate

To a solution methyl 6-amino-5-bromopyridine-2-carboxylate (20.04 g) inacetic acid (900 ml) was added N-chlorosuccinimide (13.96 g) and theresultant solution was heated to 120° C. for 1 hour. The solution wasthen evaporated and treated with excess aqueous sodium bicarbonate andextracted with dichloromethane. The organic fraction was dried andevaporated to give the product (21.98 g).

MS (+ve ion electrospray) m/z 265 and 267 (MN⁺, 100%)

(b) Methyl7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylate

This was prepared (51%) from the ester (306a) (23.8 g) by the method ofExample (301a) to give a solid (11.8 g).

MS (+ve ion electrospray) m/z 257 (MH⁺, 100%)

(c)7-Chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylicacid

This compound was prepared (96%) from the ester (306b) (11.84 g) by themethod of Example (301b) to give a solid (9.6 g).

MS (APCI-) m/z 243 ([M−H]−, 2%), 199 ([M-COOH]−, 100%)

(d)7-Chloro-6-hydroxymethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine

This compound was prepared (70%) from the carboxylic acid (306c) by themethod of Example (301c).

MS (+ve ion electrospray) m/z 231 (MH⁺, 100%)

(e)7-Chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxaldehyde

This compound was prepared (49%) from the alcohol (306d) by the methodof Example (304e) to give a solid (2.01 g).

MS (+ve ion electrospray) m/z 229 (MH⁺, 100%)

(f) Title Compound

A mixture of the carboxaldehyde (306e) (134 mg) and the amine (300e)(187 mg) in chloroform (3 ml)/methanol (3 ml) with 3A molecular sieveswas refluxed 18 hours, cooled and treated with sodiumtriacetoxyborohydride (376 mg). After stirring overnight, the mixturewas diluted with dichloromethane (50 ml) and washed with aqueous NaHCO₃.The aqueous fraction was re-extracted with 10% methanol indichloromethane and the combined organic fractions dried (MgSO₄) andevaporated. Chromatography of the residue (CH₂Cl₂:MeOH 90:10) gave freebase of the title compound (84 mg).

¹H NMR δ(DMSO) 1.4-1.5 (2H, m), 1.7-1.9 (6H, m), 2.49-2.54 (1H, m), 3.59(2H, s), 3.89 (2H, s), 4.10 (3H, s), 6.09 (1H, s), 7.33 (1H, d), 7.95(1H, s), 8.28 (1H, d), 8.44 (1H, d), 8.69 (1H, d), 11.09 (2H, br s)

This material as a solution in dichloromethane:methanol 1:1 was treatedwith 4M HCl in dioxane (0.10 ml) and evaporated to dryness. The solidwas triturated under ether, filtered and dried under vacuum to providethe title compound (75 mg).

MS (+ve ion electrospray) m/z 529 (MH+, 100%).

Example 3071-Hydroxy-t-4-[(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridine-2-ylmethyl)-amino]-r-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridine-4-yl)-amide Dihydrochloride

(a) 6-Amino-5-((E)-ethoxycarbonyl-vinyl)-pyridine-2-carboxylic acidmethyl ester

To a degassed solution of methyl 6-amino-5-bromopyridine-2-carboxylate(1.06 g), ethyl acrylate (2.49 ml), tri-o-tolylphosphine (280 mg),triethylamine (3.18 ml) in dimethylformamide (50 ml) was addedtris(dibenzylideneacetone)palladium (0) (211 mg) and the resultantsolution was heated at 50° C. for 72 h. After stirring overnight, themixture was evaporated and the residue treated with dichloromethane (50ml) and washed with H₂O. The aqueous fraction was re-extracted with 10%methanol in dichloromethane and the combined organic fractions dried(MgSO₄) and evaporated. Chromatography of the residue (60-80 petroleumether-ethyl acetate 4:1) gave the product (360 mg, 31%).

MS (+ve ion electrospray) m/z 251 (MH+, 100%)

(b) 6-Amino-5-(2-ethoxycarbonyl-ethyl)-pyridine-2-carboxylic acid methylester

A solution of the ester (307a) (350 mg) in MeOH (50 ml) was hydrogenatedover palladium on carbon (10%) (35 mg) for 24 h. The suspension wasfiltered and evaported to give the product (345 mg, 97%).

MS (+ve ion electrospray) m/z 253 (MH+, 100%)

(c) 7-Oxo-5,6,7,8-tetrahydro-[1,8]naphthyridine-2-carboxylic acid methylester

A solution of amine (307b) (345 mg) in acetic acid (20 ml) was heated at100° C. for 1 h. The acetic acid was then evaporated to give a solid(276 mg, 98%).

MS (+ve ion electrospray) m/z 206 (MH+, 100%)

(d) 7-Oxo-5,6,7,8-tetrahydro-[1,8]naphthyridine-2-carboxylic acid

This compound was prepared (96%) from the ester (307c) (272 mg) by themethod of Example (301b) to give a solid (263 mg).

MS (APCI−) m/z 191 ([M−H]−, 1%), 147 ([M-COOH]−, 100%)

(e) 7-Hydroxymethyl-3,4-dihydro-1-H-[1,8]naphthyridin-2-one

This compound was prepared (80%) from the carboxylic acid (307d) by themethod of Example (301c).

MS (+ve ion electrospray) m/z 179 (MH⁺, 100%)

(f) 7-Oxo-5,6,7,8-tetrahydro-[1,8]napthyridine-2-carboxaldehyde

This compound was prepared (28%) from alcohol (307e) by the method ofExample (304e) to give a solid (72 mg).

MS (+ve ion electrospray) m/z 229 (MH+, 100%)

(g) Title Compound

A mixture of the carboxaldehyde (307f) (72 mg) and amine (300e) (130 mg)in methanol (5 ml)/dimethylformamide (5 ml)/acetic acid (0.5 ml) washeated at 80° C. with 3A molecular sieves for 3 hours, cooled andtreated with sodium cyanoborohydride (0.6 g; 9.5 mmol). After stirringovernight at room temperature, the mixture was diluted withmethanol-chloroform (1:1), filtered and the filtrate evaporated todryness. It was treated with aqueous sodium carbonate and extracted (4×)with methanol-chloroform (1:9), dried (sodium sulfate), and evaporatedto dryness. Chromatography of the residue (0-10%methanol-dichloromethane) gave free base of the title compound (102 mg;52%).

1H NMR δ(DMSO) 1.4-1.5 (2H, m), 1.7-1.9 (6H, m), 2.47-2.51 (1H, m),2.83-2.87 (2H, t), 3.17-3.31 (4H, m), 3.75 (2H, s), 4.10 (3H, s), 6.08(1H, s), 7.04 (1H, d), 7.33 (1H, d), 7.54 (2H, m), 8.27 (1H, d), 8.44(1H, d), 8.68 (1H, d), 10.32, 11.08.

This material as a solution in chloroform/methanol 1:1 was treated withexcess 4M HCl in dioxan and evaporated to dryness. The solid wastriturated with ether, filtered and dried in vacuo to give the titlecompound, as a white solid.

MS (+ve ion electrospray) m/z 477 (MH+)

Example 3081-Hydroxy-t-4-[(7-fluoro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)-amino]-r-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide dihydrochloride

(a) Methyl 6-amino-5-bromo-3-fluoropyridine-2-carboxylate

A mixture of methyl 6-amino-5-bromopyridine-2-carboxylate (19.8 g) (T.R. Kelly and F. Lang, J. Org. Chem. 61, 1996, 4623-4633) and1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) (34.3 g) in acetonitrile (340 ml) under argon washeated to 40° C. for 1 hour, 60° C. for 1 hour and then 80° C.overnight. After partitioning between EtOAc and water (500 ml each) theaqueous fraction was re-extracted with EtOAc (300 ml) and the combinedorganic solution dried with MgSO₄ and evaporated. Chromatography (20%then 30% EtOAc in hexane) separated various byproducts from the requiredester (2.09 g).

MS (+ve ion electrospray) m/z 249 and 251 (MH⁺, 100%)

(b) Methyl6-amino-5-ethoxycarbonylmethylthio-3-fluoropyridine-2-carboxylate

A solution of ethyl mercaptoacetate (1.15 ml) in DMF (40 ml) wasice-cooled under argon, treated with sodium hydride (420 mg of a 60%dispersion in oil) and stirred until all was in solution (about 1 hour).The ester (308a) (2.48 g) was added, the mixture allowed to warm to roomtemp. and stirred overnight. EtOAc (150 ml) was added, the solutionwashed with water (3×150 ml), dried and evaporated. Chromatography ofthe residue (30 then 40% EtOAc in hexane) gave the product as an oil(1.7 g).

MS (+ve ion electrospray) m/z 289 (MH⁺, 100%)

(c) Methyl7-fluoro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylate

A solution of the fluoropyridine (308b) (1.7 g) in acetic acid (100 ml)was heated at 110° C. overnight, evaporated and dried under vacuum togive the product as a white solid (1.55 g, containing 0.33 equivalent ofacetic acid).

MS (+ve ion electrospray) in/z 243 (MH⁺, 85%), 211 (100%)

(d)7-Fluoro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylicacid

This compound was prepared from the ester (308c) by the method ofExample (301b) (86%).

(e)7-Fluoro-6-hydroxymethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine

This compound was prepared from carboxylic acid (308d) by the method ofExample (301c) (73%).

MS (−ve ion electrospray) m/z 213 ([M−H]⁻, 100%)

(f)7-Fluoro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxaldehyde

A mixture of the 7-fluoro-pyridothiazinone (308e) (971 mg), manganesedioxide (3.72 g), THF (70 ml) and 1,2-dichloroethane (70 ml) was heatedat 60° C. under argon for 20 hours. Filtration through kieselguhr andevaporation of solvent gave a solid which was triturated underEtOAc/hexane 1:3 and collected (608 mg).

MS (+ve ion electrospray) m/z 213 (MH⁺, 100%)

(g) Title Compound

A mixture of the carboxaldehyde (308f) (94 mg) and the amine (300e) (120mg) in chloroform (2.5 ml)/methanol (2.5 ml) with 3A molecular sieveswas refluxed 18 hours, cooled and treated with sodiumtriacetoxyborohydride (285 mg). After stirring for 6 hours, the mixturewas filtered, diluted with chloroform (20 ml) and washed with aqueousNaHCO₃. The aqueous fraction was re-extracted with 10% ethanol inchloroform and the combined organic fractions dried (MgSO₄) andevaporated. Chromatography of the residue (CHCl₃/MeOH/NH₄OH 95:5:0.5)gave the free base of the title compound (117 mg).

¹H NMR δ(CDCl₃/CD₃OD) 1.5-1.7 (2H, m), 1.8-2.0 (4H, m), 2.0-2.2 (2H, m),2.6-2.7 (1H, m), 3.50 (2H, s), 3.93 (2H, s), 4.16 (3H, s), 7.21 (1H, d),7.47 (1H, d), 8.16 (1H, d), 8.55 (1H, d), 8.63 (1H, d)

This material as a solution in chloroform/ethanol 1:1 was treated with1M HCl in ether (0.5 ml) and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thetitle compound (135 mg).

MS (+ve ion electrospray) m/z 513 (MH⁺, 100%)

Example 3091-Hydroxy-t-4-[(2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazin-7-ylmethyl)-amino]-r-cyclohexanecarboxylicacid (6-methyl-[1,5]naphthyridin-4-yl)-amide

(a) 5-Hydroxy-2-methylpyridine N-oxide

5-Hydroxy-2-methylpyridine (25 g) was suspended in chloroform (500 ml)and treated with m-chloroperbenzoic acid (57 g of material described as57-86% pure). After stirring for 1 hour the solution was dried withMgSO₄ and poured onto a silica column. Elution with EtOAc to removebyproducts and then with 20-50% EtOH in EtOAc gave the product (27.7 g).

MS (APCI⁺) m/z 126 (MH⁺, 60%), 109 (100%)

(b) 5-Methoxycarbonylmethoxy-2-methylpyridine N-oxide

A solution of the pyridine N-oxide (309a) (21.12 g) in DMF (450 ml) wastreated with potassium carbonate (26.2 g) and, after 30 mins., withmethyl bromoacetate (16 ml), and stirred overnight. Solvent wasevaporated, saturated brine (500 ml) added and the mixture extractedwith chloroform (6×200 ml). The combined organic solution was dried andevaporated and the residue chromatographed (20% EtOH in EtOAc) to giveproduct (18.5 g).

MS (APCI⁺) m/z 198 (MH⁺, 100%)

(c) 5-Carboxymethoxy-2-methyl-4-nitropyridine N-oxide

The pyridine N-oxide (309b) (18.5 g) was dissolved in a cold mixture offuming nitric acid (90 ml) and conc. sulfuric acid (90 ml) and heated to40° C. for 1 hour, then 65° C. overnight. The mixture was cooled, pouredonto ice and EtOAc (250 ml) added. When the ice had melted, the mixturewas shaken and solid filtered off. The EtOAc was dried and evaporated,the residue triturated under ether and solid filtered. The solidsfiltered off were combined, giving the product (8.4 g).

MS (+ve ion electrospray) m/z 229 (MH⁺, 70%), 154(100%)

(d) 5-Methoxycarbonylmethoxy-2-methyl-4-nitropyridine N-oxide

The carboxylic acid (309c) (8.4 g) in DMF (100 ml) was treated withpotassium carbonate (7.6 g) and iodomethane (2.8 ml) and stirred for 3days. After evaporation of solvent, water (200 ml) was added, themixture stirred 10 mins. and solid filtered off and dried under vacuumto give the product (5.32 g).

MS (+ve ion electrospray) m/z 243 (MH⁺, 100%)

(e) 5-Methoxycarbonylmethoxy-4-nitro-2-trifluoroacetoxymethylpyridine

The pyridine N-oxide (309d) (3.8 g) in trifluoroacetic anhydride (120ml) was refluxed under argon for 24 hours, the solvent evaporated andthe residue partitioned between chloroform and aqueous NaHCO₃ (50 mleach). The aqueous fraction was re-extracted with chloroform (3×50 ml)and the combined organic solution dried and evaporated to give theproduct (1.8 g).

MS (+ve ion electrospray) m/z 339 (MH⁺, 100%)

(f) Mixture of5-methoxycarbonylmethoxy-4-nitro-2-trifluoroacetoxymethylpyridine and2-hydroxymethyl-5-methoxycarbonylmethoxy-4-nitropyridine

When material (309e) was chromatographed on silica gel, partial loss oftrifluoroacetyl group occurred to give the product mixture.

(g) 7-Acetoxymethyl-2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine

The mixture of nitropyridines (309f) (7.37 mmole) in acetic acid (55 ml)was treated with iron powder (4.2 g) and stirred at 60° C. for 1 hour,cooled and filtered through kieselguhr. The filtrate was heated to 110°C. overnight, evaporated to dryness and partitioned between chloroformand aqueous NaHCO₃(100 ml each). After filtration to remove iron saltsand separation of the layers, the aqueous fraction was re-extracted withchloroform (10×50 ml) and the combined organic solution dried andevaporated to give product (1.17 g).

MS (−ve ion electrospray) m/z 221 ([M−H]⁻, 100%)

(h) 7-Hydroxymethyl-2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine

A solution of acetate (309g) (1.17 g) in dioxan (75 ml)/water (15 ml)was treated dropwise with 2M NaOH solution (3 ml) and left overnight.The pH was reduced to 6 with dilute HCl and the solvent evaporated.Water (5 ml) was added, the pH readjusted to 6 and the solid filteredoff and dried under vacuum to give product (877 mg).

MS (−ve ion electrospray) m/z 179 ([M−H]⁻, 100%)

(i) 2-Oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine-7-carboxaldehyde

A mixture of the hydroxymethyloxazinone (309h) (584 mg), manganesedioxide (2.3 g), THF (50 ml) and 1,2-dichloroethane (50 ml) was heatedat 60° C. under argon for 20 hours. Filtration through kieselguhr andevaporation of solvent gave a solid which was triturated underEtOAc/hexane 1:3, filtered off and dried (383 mg).

MS (−ve ion electrospray) m/z 177 ([M−H]⁻, 100%)

(j) Title Compound

A mixture of the carboxaldehyde (309i) (68 mg) and the amine (300e) (120mg) in chloroform (2.5 ml)/methanol (2.5 ml) with 3A molecular sieveswas refluxed 18 hours, cooled and treated with sodiumtriacetoxyborohydride (285 mg). After stirring for 3 hours at room temp.and 1 hour at 60° C., the mixture was filtered, diluted with chloroform(20 ml) and washed with aqueous NaHCO₃. The aqueous fraction wasre-extracted with 10% ethanol in chloroform (6×10 ml) and the combinedorganic fractions dried (MgSO₄) and evaporated. Chromatography of theresidue on silica gel (CHCl₃/MeOH/NH₄OH 95:5:0.5) gave the free base ofthe title compound (92 mg).

¹H NMR δ(CDCl₃/CD₃OD) 1.5-1.7 (2H, m), 1.8-2.0 (4H, m), 2.0-2.2 (2H, m),2.6-2.7 (1H, m), 3.85 (2H, s), 4.17 (3H, s), 4.68 (2H, s), 6.89 (1H, s),7.20 (1H, d), 8.13 (1H, s), 8.18 (1H, d), 8.54 (1H, d), 8.61 (1H, d)

This material as a solution in chloroform/ethanol 1:1 was treated with1M HCl in ether (0.4 ml) and evaporated to dryness. The solid wastriturated under ether, filtered and dried under vacuum to provide thetitle compound (98 mg).

MS (+ve ion electrospray) m/z 479 (MH⁺, 100%)

Example 3101-Hydroxy-t-4-[(7-methyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)-amino]-r-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide dihydrochloride

(a) Methyl7-methyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylate

Methyl7-bromo-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylate(Example 304b) (1.50 g, 4.95 mmol), tetramethyltin (1.71 mL, 12 mmol)and bis(triphenylphosphine)palladium(II) chloride (0.84 g, 1.2 mmol) indimethylformamide (30 mL) were heated at 120° C. for 24 h. The mixturewas filtered through Kieselguhr, washed through with ethyl acetate andevaporated. Chromatography on silica gel (10-50% ethyl acetate/petroleumether) gave the title compound (1.0 g, 85%).

MS (+ve ion electrospray) m/z 239 (MH⁺)

(b)7-Methyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylicacid

Aqueous sodium hydroxide (2M, 2.5 mL, 5 mmol) was added slowly to astirred suspension of ester (310a) (0.99 g, 4.16 mmol) intetrahydrofuran (25 mL). The mixture, which gradually formed a clearsolution, was stirred at room temperature for 24 h, then extracted withethyl acetate. The aqueous phase, containing a heavy precipitate, wasacidified to pH2 and extracted several times with ethylacetate/methanol. The extracts were dried and evaporated to give theproduct (0.87 g, 93%).

MS (+ve ion electrospray) m/z 225 (MH⁺)

(c)6-Hydroxymethyl-7-methyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine

This compound was prepared from acid (310b) (0.87 g, 3.9 mmol) by themethod of Example (301c). After neutralisation, the mixture wasextracted several times with ethyl acetate. The extracts were dried andevaporated and the residue was chromatographed on silica (1:1 ethylacetate/hexane, then ethyl acetate) to give a solid (0.48 g, 59%).

MS (+ve ion electrospray) m/z 211 (MH⁺)

(d)7-Methyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxaldehyde

A solution of alcohol (310c) (0.47 g, 2.2 mmol) in dichloromethane (50mL) was stirred with manganese dioxide (2.8 g) at room temperature for16 h. The mixture was filtered through Kieselguhr, washed through withdichloromethane/methanol and evaporated to give the title compound (0.34g), containing some of the corresponding methyl hemiacetal.

MS (+ve ion electrospray) m/z 209 (MH⁺)

(e) Title compound

The aldehyde (310d) (0.13 g, 0.63 mmol) and amine (Example 300e) (0.20g, 0.63 mmol) in anhydrous chloroform/dimethylformamide/methanol(10:5:1, 16 mL) was heated over 3A molecular sieves at 100° C. for 16 h.After cooling, sodium (triacetoxy)borohydride (0.60 g) was added and themixture was stirred at room temperature for 3 days. The mixture wasbasified with sodium bicarbonate and diluted with dichloromethane andwater. The aqueous phase was extracted several times with 10%methanol/dichloromethane and the combined organics were washed withwater, dried and evaporated. Chromatography on silica gel (5-8%methanol/dichloromethane) gave the free base of the title compound(0.143 g, 45%).

¹H NMR δ(CDCl₃) 1.9-2.2 (8H, m), 2.13 (3H, s), 2.96 (1H, m), 3.38 (2H,s), 3.99 (3H, s), 4.02 (2H, s), 7.06(1H, d), 7.31(1H, s), 8.15(1H, d),8.46 (1H, d), 8.62 (1H, d), 11.04(1H, s)

MS (+ve ion electrospray) m/z 509 (MH⁺)

The free base in chloroform was treated with 2 equivalents of 0.4 Mhydrochloric acid in dioxan. Evaporation of solvent and trituration withether gave the dihydrochloride salt.

Example 3111-Hydroxy-t-4-[(7-ethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)-amino]-r-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide dihydrochloride

(a) Methyl7-ethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylate

Methyl7-bromo-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylate(Example 304b) (2.00 g, 6.6 mmol), tetraethyltin (3.17 mL, 16 mmol) andbis(triphenylphosphine)palladium(II) chloride (1.12 g, 1.6 mmol) indimethylformamide (40 mL) were heated at 120° C. for 24 h. The mixturewas filtered through Kieselguhr, washed through with ethyl acetate andevaporated. Chromatography on silica gel (20-50% ethyl acetate/petroleumether) gave a mixture of the 7-ethyl and 7-vinyl compounds (0.29 g).This mixture was hydrogenated in methanol/ethyl acetate (2:1, 60 mL)over 10% palladium on carbon (60 mg) (1 atmosphere, room temperature)for 24 h. Filtration and evaporation of solvent gave the product (0.28g).

MS (+ve ion electrospray) m/z 253 (MH⁺)

(b) 7-Ethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylicacid

Aqueous sodium hydroxide (2M, 0.67 mL, 1.33 mmol) was added slowly to astirred suspension of ester (311a) (0.28 g, 1.11 mmol) intetrahydrofuran (10 mL). The mixture was stirred at room temperature for16 h, then additional sodium hydroxide (2M, 0.4 mL, 0.8 mmol) was added.After stirring for another 8 h, the mixture was evaporated. The residuewas dissolved in water. acidified to pH3 and the precipitate wasfiltered off, washed with water and dried to give a solid (0.25 g, 95%).

MS (+ve ion electrospray) m/z 239 (MH⁺)

(c)7-Ethyl-6-hydroxymethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine

This compound was prepared from acid (311b) (0.25 g, 1.05 mmol) by themethod of Example (310c). Chromatography on silica gel (ethyl acetate)gave the alcohol (0.11 g, 47%).

MS (+ve ion electrospray) m/z 225 (MH⁺)

(d)7-Ethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxaldehyde

A solution of alcohol (311c) (0.11 g, 0.49 mmol) in dichloromethane (10mL) was stirred with manganese dioxide (0.7 g) at room temperature for16 h. The mixture was filtered through Kieselguhr, washed through withdichloromethane/methanol and evaporated to give the title compound(0.078 g), containing some of the corresponding methyl hemiacetal.

MS (+ve ion electrospray) m/z 223 (MH⁺)

(e) Title Compound

The aldehyde (311d) (0.078 g, 0.35 mmol) and amine (Example 300e) (0.11g, 0.35 mmol) in dimethylformamide/methanol/acetic acid (10:10:1, 11.5mL) was heated over 3A molecular sieves at 80° C. for 4 h. Aftercooling, sodium cyanoborohydride (0.066 g, 1.05 mmol) was added and themixture was stirred at room temperature for 16 h. The mixture wasevaporated and the residue was basified with sodium bicarbonate, dilutedwith water and extracted several times with 10%methanol/dichloromethane. The combined organics were dried andevaporated. Chromatography on silica (2-10% methanol/dichloromethane)gave the free base of the title compound (0.082 g, 45%).

¹H NMR δ(CDCl₃/CD₃OD) 1.25 (3H, t), 1.68(2H, q), 1.88(2H, d), 1.97(2H,d), 2.08(2H, m), 2.65(2H, q), 2.70 (1H, m), 3.49 (2H, s), 3.90(2H, s),4.17 (3H, s), 7.24(1H, d), 7.68(1H, s), 8.18(1H, d), 8.54 (1H, d), 8.62(1H, d)

MS (+ve ion electrospray) m/z 523 (MH⁺)

The free base in chloroform/methanol was treated with 2 equivalents of0.4M hydrochloric acid in dioxan. Evaporation of solvent and triturationwith ether gave the dihydrochloride salt.

Example 3121-Hydroxy-t-4-[(6-oxo-6,7-dihydro-5H-pyridazino[3,4-b][1,4]thiazin-3-ylmethyl)-amino]-r-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide dihydrochloride

(a) 4-Amino-3,6-dichloropyridazine

A suspension of 3,4,6-trichloropyridazine (prepared by the method of B.Kasnar et al, Nucleosides and Nucleotides, 1994, 13, 459) (10.0 g) inconc. aqueous ammonia (1 L) was heated at 75° C. for 16 h. The mixturewas concentrated to a small volume and extracted several times withethyl acetate. The extracts were washed with brine, dried andevaporated. The crude product was recrystallised from ethyl acetate togive the product (5.03 g).

(b) 3-Chloro-6-oxo-6,7-dihydro-5H-pyridazino[3,4-b][1,4]thiazine

To a well-stirred suspension of sodium hydride (60% in mineral oil, 0.35g, 8.5 mmol) in anhydrous dimethylformamide (10 mL) at 0° C. was addedmethyl mercaptoacetate (0.70 mL, 7.9 mmol). After stirring at thistemperature for 20 min, a solution of amine (312a) (1.29 g, 7.87 mmol)in dimethylformamide (10 mL) was added. The mixture was stirred at roomtemperature for 16 h, then most of the solvent was removed in vacuo. Theresidue was diluted with water, the precipitate was filtered off, washedwith water and dried. Chromatography on silica gel (0-2%methanol/dichloromethane) gave the product (0.21 g, 13%).

MS (+ve ion electrospray) m/z 202/204 (MH⁺)

(c) 6-Oxo-3-vinyl-6,7-dihydro-5H-pyridazino[3,4-b][1,4]thiazine

To a mixture of the pyridazinothiazinone (312b) (0.15 g, 0.75 mmol),bis(triphenylphosphine)palladium(II) chloride (84 mg, 0.12 mmol) andlithium chloride (63 mg, 1.2 mmol) in dimethylformamide (3 mL) was addedtributyl(vinyl)tin (0.36 mL, 1.2 mmol). The mixture was heated at110-120° C. for 16 h, then evaporated. The residue was partitionedbetween water and ethyl acetate, the aqueous phase was extracted furtherwith ethyl acetate and the combined organics were dried and evaporated.Chromatography on silica gel (0-3% methanol/dichloromethane) gave theproduct (45 mg, 31%).

MS (+ve ion electrospray) m/z 194 (MH⁺)

(d) 6-Oxo-6,7-dihydro-5H-pyridazino[3,4-b][1,4]thiazine-3-carboxaldehyde

To a suspension of vinyl compound (312c) (0.6 g, 3.35 mmol) in1,4-dioxan (60 mL) was added osmium tetroxide (4% in water, 2 mL, 0.335mmol), sodium periodate (1.43 g, 6.7 mmol) and water (20 mL). Themixture was stirred at room temperature for 7 h, then diluted with waterand dichloromethane and phases separated. The aqueous phase wasextracted twice with 10% methanol/dichloromethane and the combinedorganics were dried and evaporated. Chromatography on silica gel (0-2%methanol/dichloromethane) gave the aldehyde (0.206 g), containing someof the corresponding methyl hemiacetal.

(e) Title Compound

The aldehyde (312d) (84 mg, 0.4 mmol) and amine (300e) (0.13 g, 0.4mmol) in 1:1 methanol/chloroform (10 mL) were stirred over 3A molecularsieves at 65° C. for 16 h. The cooled mixture was diluted with 1:1methanol/chloroform (20 mL) and sodium (triacetoxy)borohydride (excess)was added. The mixture was stirred over 5 days with periodic furtheradditions of sodium (triacetoxy)borohydride. The mixture was thendiluted with chloroform, filtered and evaporated to a small volume. Theresidue was basified with aqueous sodium carbonate and extracted fourtimes with 10% methanol/chloroform. The extracts were dried andevaporated, and the residue was chromatographed on silica gel (2-10%methanol/dichloromethane) to give the free base of the title compound(31 mg, 16%).

¹H NMR δ(CDCl₃/CD₃OD) 1.61(2H, m), 1.80-2.15(6H, m), 2.65 (1H, m), 3.70(2H, s), 4.06(2H, s), 4.17(3H, s), 7.04(1H, s), 7.22(1H, d), 8.18(1H,d), 8.54 (1H, d), 8.62 (1H, d)

MS (+ve ion electrospray) 7 m/z 496 (MH⁺)

The free base in chloroform/methanol was treated with 2 equivalents of4M hydrochloric acid in dioxan. Evaporation of solvent and triturationwith ether gave the dihydrochloride salt.

Example 3131-Hydroxy-t-4-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)-amino]-r-cyclohexanecarboxylicacid [6-(2-methoxy-ethoxy)-[1,5]naphthyridin-4-yl]-amide dihydrochloride

(a) 6-(2-Methoxy-ethoxy)-[1,5]naphthyridin-4-ylamine

This was prepared in 42% yield (1.9 g) from Example (29a) according tothe procedure for (29b) with 2-bromoethylmethyl ether as the alkylatingagent.

MS (+ve ion electrospray) m/z 220 (MH+).

(b) 8-Bromo-2-(2-methoxy-ethoxy)-[1,5]naphthyridine

A solution of (313a) (1.9 g, 8.7 mmol), copper(II) sulphate (4.2 g, 26.1mmol) and sodium bromide (3.6 g, 34.8 mmol) in 9M sulphuricacid/methanol (35 ml/18 ml) was treated at 0° C. with a solution ofsodium nitrite (0.9 g, 13.1 mol) in water (18 ml). The mixture wasallowed to come to room temperature over 0.5 hour, then heated at 40° C.for 0.5 hour. The mixture was partitioned between dilute aqueous sodiumhydroxide solution and ethyl acetate. The organic extract was dried,filtered and evaporated. The residue was chromatographed on silicaeluting with 0-50% ethyl acetate in dichloromethane affording an oil(1.1 g, 45%).

MS (+ve ion electrospray) m/z 284 (MH+).

(c){r-4-Hydroxy-4-[6-(2-methoxy-ethoxy)-[1,5]naphthyridin-4-ylcarbamoyl]-c-cyclohexyl}-carbamicacid tert-butyl ester

This was prepared in approximately quantitative yield (1.8 g) from(313b) according to the procedure of Example (300d).

MS (+ve ion electrospray) m/z 461 (MH+).

(d) t-4-Amino-1-hydroxy-r-cyclohexanecarboxylic acid[6-(2-methoxy-ethoxy)-[1,5]naphthyridin-4-yl]-amide

This was prepared from (313c) in 40% yield (280 mg) by treatment withtrifluoroacetic acid followed by a basic workup according to theprocedure of Example (300e).

MS (+ve ion electrospray) m/z 361 (MH+).

(e) Title Compound

This was prepared from amine (313d) and aldehyde (301d) by reductivealkylation with sodium cyanoborohydride according to the procedure ofExample (357), affording the free base of the title compound as a whitesolid (62 mg, 29%)

δH (CDCl₃, 250 MHz): 8.62 (1H, d), 8.45 (1H, d), 8.15 (1H, d), 7.55 (1H,d), 7.15 (1H, d), 6.90 (1H, d), 4.65 (2H, m), 4.00 (2H, s), 3.85 (2H,s), 3.80 (2H, m), 3.45 (2H, s), 3.30 (3H, s), 2.65 (1H, m), 2.20-1.50(8H, m)

MS (+ve ion electrospray) m/z 539 (MH+).

This was converted to the title compound (70 mg) by the same procedureas for Example 300.

Example 3141-Hydroxy-t-4-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)-amino]-r-cyclohexanecarboxylicacid (2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-10-yl)-amidedihydrochloride

(a) 7-Bromo-2,3-dihydro-benzo[1,4]dioxin-6-ylamine

A solution of 2,3-dihydro-benzo[1,4]dioxin-6-ylamine (32 g, 212 mmol) indichloromethane (1 liter) was treated with a solution of bromine (10.8ml, 212 mmol) in dichloromethane (100 ml) at 0° C. After the additionthe mixture was stirred at room temperature for 1 hour then washed withsaturated aqueous sodium bicarbonate solution containing a small amountof sodium sulphite. The organic organic extract was dried and evaporatedaffording an oil that was chromatographed on silica gel eluting withdichloromethane to afford an oil (14.8 g, 30%).

MS (+ve ion electrospray) m/z 231 (MH+).

(b)5-[(7-Bromo-2,3-dihydro-benzo[1,4]dioxin-6-ylamino)-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione

A mixture of aniline (314a) (14.8 g, 64.3 mmol), triethyl orthoformate(12.7 ml, 77.2 mmol) and 2,2-dimethyl-[1,3]dioxane-4,6-dione (Meldrum'sacid) (11.1 g, 77.2 mmol) in ethanol (70 ml) was heated to reflux. After1 hour the mixture was allowed to cool to room temperature thenfiltered, washing with ethanol then ether, to afford a white solid (22.9g, 93%).

MS (+ve ion electrospray) m/z 385 (MH+).

(c) 6-Bromo-2,3-dihydro-7H-[1,4]dioxino[2,3-f]quinolin-10-one

Enamine (314b) (22.9 g) was added portionwise to refluxing Dowtherm A(45 ml) over 3 minutes. After a further 3 minutes at reflux the mixturewas cooled to room temperature. Ethyl acetate/hexane (10 ml/20 ml) wasadded and a black solid isolated by filtration. This residue wasdissolved in hot methanol (400 ml) and filtered through Keiselguhr.Water (800 ml) was added and the mixture stored at 5° C. overnight.Filtration and drying afforded a pale yellow solid (10.3 g, 61%).

MS (APCI⁻) m/z 281 [M−H]⁻

(d) 2,3-Dihydro-7H-[1,4]dioxino[2,3-f]quinolin-10-one

A suspension of (314c) (3.4 g, 12 mmol) in water/dioxan (150 ml/80 ml)was treated with 1M aqueous sodium hydroxide solution then hydrogenatedover 10% palladium on charcoal (1.5 g) for 20 hours. The mixture wasfiltered then acidified with 5M aqueous hydrochloric acid. Onconcentrating to ca 100 ml, a solid began to crystallise out. Themixture was stored at 5° C. overnight. Filtration and drying afforded apale yellow solid (2.8 g, 100%).

MS (APCI⁻) m/z 202 [M−H]⁻

(e) 10-Bromo-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline

A mixture of (314d) (2.5 g) and phosporus oxybromide (7.8 g) was heatedat 120° C. for 0.75 hour. After cooling to room temperature the mixturewas treated with water, basified with potassium carbonate and extractedwith ethyl acetate. The organic extract was dried and evaporated toafford an oil (475 mg, 14%).

MS (+ve ion electrospray) m/z 268 (MH+).

(f)[4-(2,3-Dihydro-[1,4]dioxino[2,3-f]quinolin-10-ylcarbamoyl)-r-4-hydroxy-c-cyclohexyl]-carbamicacid tert-butyl ester

This was prepared in 25% yield (0.2 g) from (314e) according to theprocedure of Example (300d).

MS (+ve ion electrospray) m/z 444 (MH+).

(g) t-4-Amino-1-hydroxy-c-cyclohexanecarboxylic acid(2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-10-yl)-amide

This was prepared from carbamate (314f) in 52% yield (80 mg) bytreatment with trifluoroacetic acid followed by a basic workup,according to the procedure of Example (300e).

MS (+ve ion electrospray) m/z 344 (MH+).

(h) Title Compound

This was prepared from amine (314 g) and aldehyde (301d) by reductivealkylation with sodium cyanoborohydride according to the procedure ofExample (357) to afford the free base of the title compound as a whitesolid (21 mg, 17%).

δH (CD₃OD, 250 MHz): 8.60 (1H, d), 8.50 (1H, d), 7.65 (1H, d), 7.50 (1H,d), 7.35 (1H, d), 7.05 (1H, d), 4.55 (2H, m), 4.42 (2H, m), 4.15 (2H,s), 3.50 (2H, s), 2.62 (1H, m), 2.20-1.50 (8H, m)

MS (+ve ion electrospray) m/z 522 (MH+).

This was converted to thetitle compound (18 mg) by the same procedure asfor Example (300).

Unless otherwise stated, the following Examples were prepared from amine(300e) and the appropriate carboxaldehyde by analogous methods to thatof Example (300f)

salt B Dihydrochloride Method of A Hydrochloride synthesis R Example(aldehyde) Trihydrochloride R 320 a B

321 B

322 (Example 9e) B

323 (Example 32d) B

324 b B

325 (Example 19d) B

326 c B

327 (mesylate 6b) B

328 d B

329 (Example 20e) B

330 e B

331 f R

332 g A

333 h B

334 cis-isomer B

335 (Example 25b) B

336 j B

337 (Example 16d) B

338 k B

339 l B

340 m B

341 n B

342 o B

343 p

a Prepared from 4-fluoro-1H-benzoimidazole-2-carboxaldehyde, itselfprepared from 3-fluoro-benzene-1,2-diamine by reaction with glycolicacid followed by oxidation with manganese dioxide b7-Fluoro-2,3-dihydro-benzo[1,4]dioxine-6-carboxaldehyde prepared from6-fluoro-2,3-dihydro-benzo[1,4]dioxine [V. Daukas et al Chemija, 1999,10 (1), 59] by reaction of dichloromethyl methyl ether and titaniumtetrachloride - see Example 213. c Prepared by reacting ester (13b) withlithium aluminium hydride followed by oxidation with manganese dioxideto give the carboxaldehyde d Prepared by reacting3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid methyl esterwith lithium aluminium hydride followed by oxidation with manganesedioxide to give the carboxaldehyde e Prepared by reacting ester (301a)with lithium aluminium hydride followed by oxidation with manganesedioxide to give the carboxaldehyde f Prepared by reacting (305e) withlithium aluminium hydride followed by oxidation with manganese dioxideto give the carboxaldehyde g5,6,7,8-Tetrahydro-[1,8]naphthyridine-2-carboxaldehyde preparedaccording to the procedure of WO 98/08840 h Prepared from[1,2,3]thiadiazolo[5,4-b]pyridine-6-carboxaldehyde, itself prepared from(302b) by reaction with sodium benzylmercaptan in dioxan, heating inacetic anhydride to form the acetoxymethyl-pyridine, reducing the nitrogroup with iron in acetic acid at 60° C., reaction with sodium nitritein cold dilute hydrochloric acid to form the thiadiazole ring, andoxidising the resulting alcohol with manganese dioxide. i Prepared from(4-carbamoyl-r-4-hydroxy-t-cyclohexyl)-carbamic acid tert-butyl ester(see Example 300c-faster running isomer) by the method of Example(300d-f) j The carboxaldehyde was prepared by heating amine (16a) withacetic anhydride/acetic acid/sodium acetate to afford the2-methylthiazole, followed by reduction of the ester with lithiumaluminium hydride at −30° C., followed by oxidation with manganesedioxide k The carboxaldehyde was prepared from the zinc salt of4-mercapto-3-nitro-benzoic acid ethyl ester by heating in aceticanhydride followed by reduction of the ester with lithium aluminiumhydride at −30° C., followed by oxidation with manganese dioxide. lPrepared by reaction of amine (300e) with2-chloromethyl-pyrimido[1,2-a]pyrimidin-4-one in DMF containinganhydrous potassium carbonate (by the method of Example 26). m Preparedfrom Example (19c) by nitration, manganese (II) oxidation to give8-nitro-2,3-dihydro-benzo[1,4]dioxine-6-carbaldehyde, reductiveailcylation with amine (300e) according to the method of Example (300f),and finally hydrogenation of the nitro group to amino giving the freebase of the title compound. n Prepared from Example (304a) by reactionwith the sodium salt of 3-mercapto-propionic acid ethyl ester tounexpectedly give 6-amino-3-bromo-5-mercapto-pyridine-2-carboxylic acidmethyl ester, followed by cyclisation with formic acid at 100° C. togive the thiazolopyridine, which was debrominated by hydrogenation (Pd/Cin ethanol). Treatment of the ester with LiAlH4 in THF gave thethiazolo[45-b]pyridine-5-carboxaldehyde, # which was converted toExample (341). o Prepared from5-benzyloxy-2-hydroxymethyl-1H-pyridin-4-one (T. Teitei, Aust. 3. Chem.,1983, 36, (11), 2307) by chlorination with N-cblorosuccinimide in aceticacid to give 5-benzyloxy-3-chloro-2-hydroxymethyl-1H-pyridin-4-one,followed by hydrogenation to remove the benzyl group and reaction with1,2-dibromoethane and potassium carbonate to give(8-cbloro-2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl)-methanol,followed by oxidation with manganese # (II)oxide to give8-chloro-2,3-dihydro-[1,4]dioxino[2,3-c]pyridine-7-carboxaldehyde,followed by reductive alkylation with amine (300e) according to themethod of Example (300k) giving the free base of the title compound. pPrepared from 5-benzyloxy-2-hydroxymethyl-3H-pyrimidin-4-one (A. Harris,Aust. J. Chem., 1976, 29, 1335) by hydrogenolysis of the beuzylprotecting group and cydlisation with dibromoethane to give(6,7-dihydro-[1,4]dioxmo[2,3-d]pyrimidin-2-yl)-methanol followed byoxidation with manganese(II)oxide to give6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine-2-carbaldehyde and reductivealkylation with amine 300e according to the method of Example (300f)

Example 350(1S,3S,4S)-3-Hydroxy-4-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide dihydrochloride and(1R,3R,4R)-3-Hydroxy-4-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide dihydrochloride

(a) (1R,3S,4S)— and(1S,3R,4R)-4-tert-Butoxycarbonylamino-3-hydroxy-cyclohexanecarboxylicacid methyl ester

This was prepared essentially as described by K. Krajewski et alTetrahedron: Asymmetry 10 (1999) 4591-4598, and contained about 20% ofthe 3-tert-butoxycarbonylamino-4-hydroxy-regioisomer.

A portion was purified by silica gel chromatography (hexane-ethylacetate 2:1) and recrystallised from ether-pentane to afford crystalsthat gave an X-ray structure confirming the configuration above.

(b) (1S,3S,4S)— and(1R,3R,4R)-4-tert-Butoxycarbonylamino-3-hydroxy-cyclohexanecarboxylicacid methyl ester

The crude ester (350a) (21.19 g) in dry methanol (200 ml) was treatedwith 25% sodium methoxide in methanol (33.5 ml) and heated at 70° C. for3 days. It was cooled in ice, neutralised with 2N hydrochloric acid, andevaporated to dryness. Water was added and the resulting solidcollected, washed with water and dried to give the product (8.0 g).Extraction of the aqueous fraction with dichloromethane, followed bysilica gel chromatography (2% methanol-dichloromethane) gave a further4.3 g of less pure material.

(c) (1S,3S,4S)— and(1R,3R,4R)-4-tert-Butoxycarbonylamino-3-hydroxy-cyclohexanecarboxylicacid

The ester (350b) (2.4 g) in dioxan (100 ml) and water (5 ml) was treatedwith 2N sodium hydroxide (6.6 ml) and stirred overnight at roomtemperature. The mixture was acidified with 2N hydrochloric acid,evaporated to one quarter volume, extracted (5×) with ethyl acetate,washed with a little water, dried (sodium sulfate), and evaporated togive the product as a foam (2.4 g).

MS (−ve ion electrospray) m/z 258 (M−H⁻)

(d) ((1S,4S,5S)— and-(R,4R,5R)-7-Oxo-6-oxa-bicyclo[3.2.1]oct-4-yl)-carbamic acid tert-butylester

The carboxylic acid (350c) (26 g) in dry dichloromethane (50 ml) wastreated with triethylamine (1.01 g) and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (2.11 g)and stirred at room temperature overnight. The product was evaporated todryness, water and sodium bicarbonate were added and the solution wasextracted with dichloromethane and dried (sodium sulfate). It waschromatographed on silica gel (0.5-2% methanol-dichloromethane) toafford a white solid (0.90 g).

νmax 1,780 cm⁻¹

(e) (1S,2S,4S) and-(1R,2R,4R)-4-Carbamoyl-2-hydroxy-cyclohexyl)-carbamic acid tert-butylester

The lactone (350d) (3.14 g) in tetrahydrofuran (150 ml) was treated with32% ammonia in water (100 ml) and the mixture was well stirred overnightand evaporated to dryness to afford a solid (3.25 g).

MS (−ve ion electrospray) m/z 257 (M−H⁻)

(f) [(1S,2S,4S)— and(1R,2R,4R)-2-Hydroxy-4-(6-methoxy-[1,5]naphthyridin-4-ylcarbamoyl)-cyclohexyl]-carbamicacid

A mixture of the amide (350e) (0.215 g), cesium carbonate (0.344 g),tris(dibenzylideneacetone)dipalladium(0) (16.3 mg), andrac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (32.6 mg) in dry dioxan(9 ml) under argon, was sonicated for 10 minutes,1,1-trifluoro-methanesulfonic acid 6-methoxy-[1,5]naphthyridin-4-ylester (1b) (0.27 g) was added, and the mixture was stirred and heated at80-85° C. for 24 hours, under argon. The mixture was cooled, filtered,and the filtrate evaporated and chromatographed on silica gel, elutingwith chloroform, then (1-2%) methanol-dichloromethane, to afford a solid(0.21 g).

MS (+ve ion electrospray) m/z 417 (MH+).

(g) (1S,3S,4S)— and (1R,3R,4R)-4-Amino-3-hydroxy-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide

The carbamate (350f) (0.21 g) in dichloromethane (10 ml) was treatedwith trifluoroacetic acid (10 ml) for 2 hours and evaporated. Sodiumcarbonate solution was added and the solution was extracted (5×) with10% methanol-chloroform, dried (sodium sulfate) and evaporated to give awhite solid (0.148 g).

MS (+ve ion electrospray) m/z 317 (MH⁺).

(h) Title Compound

A mixture of carboxaldehyde (301d) (45 mg) and amine (350g) (70 mg) inchloroform (5 ml) and methanol (5 ml) with 3A molecular sieves washeated under reflux for 4 hours, cooled, treated with sodiumtriacetoxyborohydride (300 mg). and heated at 40° C. overnight. Themixture was cooled, diluted with chloroform and methanol, filtered andevaporated. The residue was treated with aqueous sodium carbonate andextracted (3×) with 10% methanol-chloroform and the combined organicfractions dried (MaSO₄), evaporated and chromatographed on silica gel,eluting with 2-10% methanol-dichloromethane to give free base of thetitle compound (80 mg).

¹H NMR δ(250 MHz, CDCl₃/CD₃OD) 1.2-1.8 (3H, m), 2.15 (2H, m), 2.35 (1H,m), 2.5 (1H, m), 2.72 (1H, m), 3.49 (2H, s), 3.55 (1H, m), 3.80 (1H, d),3.95 (1H, d), 4.17 (3H, s), 6.96 (1H, d), 7.23 (1H, d), 7.62 (1H, d),8.20 (1H, d), 8.50 (1H, d), 8.65 (1H, d)

MS (+ve ion electrospray) m/z 495 (MH⁺)

The free base in chloroform/methanol (1:1) was treated with 4M HCl indioxan (0.5 ml) and evaporated to dryness. The solid was triturated withether, filtered and dried in vacuo, to provide title compound (87 mg).

The racemic free base was subjected to preparative HPLC [Chiralpak AD250 mm×20 mm i.d.; 10 micron particle size; eluent:n-hexane-ethanol(both with 0.1% DEA), 70:30 v/v; flow-rate:15.0 ml min⁻¹] to afford afaster eluting single enantiomer [retention time 13.4 mins] and a slowereluting single enantiomer [retention time 16.9 mins], both with 100% ee.

Example 351(1R,3R,4R)-3-Hydroxy-4-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide dihydrochloride

(a) (1R,4S,5R)-4-bromo-6-oxabicyclo[3.2.1]octan-7-one

(R)-Cyclohex-3-enecarboxylic acid (2.30 g, 18.2 mmol) ([α]_(D)=+83.8°(c=1, CHCl₃)=88.2% e.e., resolved by the method of Schwartz et al, J.Am. Chem. Soc., 100, 5199, (1978)) was reacted with trimethylsilylbromide and DMSO (by the method of Iwata et al, Heterocycles., 31, 987(1990)) to give a white solid, (2.13 g, 10.4 mmol, 57%);

¹H NMR δ(400 MHz, CDCl₃) 1.68 (1H, dddd), 1.86 (1H, d), 1.98-2.02 (1H,m), 2.20 (1H, dddd), 2.42 (1H, ddd), 2.50-2.56 (1H, m), 2.73 (1H, br s),4.15 (1H, dd), 4.91 (1H, d).

(b) (1R,3R,4S)-4-bromo-3-hydroxycyclohexanecarboxylic amide

(1R,4S,5R)-4-bromo-6-oxabicyclo[3.2.1]octan-7-one (351a) (2.13 g, 10.4mmol) was taken up in THF (20 mL) and treated with 0.880 ammonia (5.3mL) at 20° C. for 24 h with stirring. The solvent was then removed invacuo to give a white solid in quantitative yield; [α]_(D)=+40.6° (c=1,MeOH).

¹H NMR δ(400 MHz; CD₃OD) 1.63 (1H, dd, 1.73-1.80 (1H, m), 1.85-2.03 (3H,m), 2.16-2.21 (1H, m), 2.36 (1H, tt), 3.54 (1H, dt), 4.55 (1H, bs).

(c) (1R,3R,4R)-4-azido-3-hydroxy-cyclohexanecarboxylic acid amide

(1R,3R,4S)-4-Bromo-3-hydroxycyclohexanecarboxylic amide (351b) (2.31 g,10.4 mmol) was treated with sodium azide (1.35 g, 20.8 mmol) in DMF (100mL) at 60° C. for 15.5 h. The solvent was removed in vacuo and theresidue purified by flash column chromatography (Silica gel, DCM:MeOH0-10%) to give a white solid (1.09 g, 5.93 mmol, 57%); [α]_(D)=15.5°(c=1, MeOH).

¹H NMR δ(400 MHz; CD₃OD) 1.30 (1H, dq), 1.42-1.56 (2H, m), 1.83 (1H,dt), 1.99-2.08 (2H, m), 2.30 (1H, tt), 3.16(1H, ddd), 3.41 (1H, ddd).

(d) (1R,3R,4R)-4-amino-3-hydroxy-cyclohexanecarboxylic acid amide,acetate salt

To (1R,3R,4R)-4-azido-3-hydroxy-cyclohexanecarboxylic acid amide (351c)(765 mg, 4.15 mmol) in MeOH/AcOH (9:1, 30 mL) was added Pd/C (10%, 300mg), and the mixture hydrogenated under atmospheric pressure for 22 h.On completion of reaction the mixture was filtered through Celite®, thefilter pad washed with MeOH, and the combined organic solutionsconcentrated in vacuo to give a white solid in quantitative yield.

¹H NMR δ(400 MHz; CD₃OD) 1.42-1.59 (3H, m), 1.87-1.92 (1H, m), 1.92 (3H,s), 2.07-2.14 (2H, m), 2.37 (1H, tt), 2.84 (1H, dt), 3.50 (1H, dt).

(e) ((1R,2R,4R)-4-Carbamoyl-2-hydroxy-cyclohexyl)-carbamic acidtert-butyl ester

The amide, acetate salt (351d) (905 mg, 4.15 mmol) was treated withN,N-diisopropylethylamine (868 uL, 4.98 mmol) anddi-tert-butyl-dicarbonate (1.08 g, 4.98 mmol) in dioxane (30 mL), andMeOH (50 mL) for 16 h. The solvent was then removed in vacuo and theresidue purified by flash column chromatography (Silica gel, DCM:MeOH0-10%) to give a white solid (804 mg, 3.11 mmol, 75%); [α]_(D)=−17.0°(c=1, MeOH).

¹H NMR δ(400 MHz; CD₃OD) 1.18-1.32 (1H, m), 1.44 (9H, s), 1.43-1.55 (2H,m), 1.81 (1H, bd), 1.98 (1H, bd), 2.09 (1H, bd), 2.29 (1H, tt), 3.22(1H, dt), 3.33 (1H, dt).

(f)[(1R,2R,4R)-2-Hydroxy-4-(6-methoxy-[1,5]naphthyridin-4-ylcarbamoyl)-cyclohexyl]-carbamicacid tert-butyl ester

The amide (351e) (671 mg, 2.60 mmol) was reacted with the triflate ester(1b) (801 mg, 2.60 mmol) by the procedure of Example (350f), but carriedout at 60° C., to give a white solid (889 mg, 2.13 mmol, 82%);

¹H NMR δ(400 MHz; CD₃OD) 1.34-1.50 (1H, m), 1.46 (9H, s), 1.62-1.71 (2H,m), 2.04-2.12 (2H, m), 2.32-2.38 (1H, m), 2.70-2.78 (1H, m), 3.27-3.34(1H, m), 3.45-3.51 (1H, m), 4.15 (3H, s), 7.24 (1H, d), 8.17 (1H, d),8.47 (1H, d), 8.60 (1H, d);

MS (+ve ion electrospray) m/z 417 (MH⁺, 100%).

(g) (1R,3R,4R)-Amino-3-hydroxy-cyclohexanecarboxylic acid(6-methoxy-[1,5]naphthyridin-4-yl)-cyclohexyl]-amide

The carbamate (351f) (860 mg, 2.06 mmol) in DCM (30 mL) was treated withtrifluoroacetic acid (10 mL). After 35 min the solvent was removed invacuo and the residue purified by flash column chromatography (silicagel, DCM:MeOH/NH₃ (2M) 0-15%) to give a white solid (624 mg, 1.97 mmol,95%); [α]_(D)=−0.8° (c=1, MeOH).

¹H NMR δ(400 MHz; CD₃OD) 1.30-1.41 (1H, m), 1.57-1.70 (2H, m), 1.99-2.10(2H, m), 2.25-2.31 (1H, m), 2.53-2.59 (1H, m), 2.76-2.84 (1H, m),3.30-3.36 (1H, m), 4.17 (3H, s), 7.26 (1H, d), 8.19 (1H, d), 8.49 (1H,d), 8.61 (1H, d);

MS (+ve ion electrospray) m/z 317 (MH⁺, 100%).

(h) Title Compound

The amine (351 g) (0.664 mmol) under argon in MeOH (21 mL) and DMF (21mL) was treated with carboxaldehyde (301d) (0.664 μmol), and 3Amolecular sieves (1 g), followed by AcOH (2.1 mL). Sodiumcyanoborohydride (83 mg, 1.33 mmol) was added after 20 min. Once thereaction had gone to completion the mixture was adsorbed onto an SCXcartridge, washed with MeOH, eluted with MeOH/NH₃ (2M), and the solventremoved in vacuo from the appropriate fractions. The residue waspurified by flash column chromatography (Silica gel, DCM:MeOH/NH₃ (2M)0-12%) to give the free base of the title compound (72% yield);

¹H NMR δ(400 MHz; CDCl₃/CD₃OD) 1.23-1.33 (1H, m), 1.58-1.74 (2H, m),2.10-2.22 (2H, m), 2.32-2.38 (1H, m), 2.43-2.50 (1H, m), 2.62 (1H, tt),3.46-3.53 (1H, m), 3.48 (2H, s), 3.78, 3.95 (2H, ABq), 4.14 (3H, s),6.93 (1H, d), 7.20 (1H, d), 7.60 (1H, d), 8.20 (1H, d), 8.50 (1H, d),8.64 (1H, d);

MS (+ve ion electrospray) m/z 495 (MH⁺, 100%).

Analytical HPLC [Chiralpak AD 250 mm×4.6 mm i.d.; 10 micron particlesize; eluent: n-hexane-ethanol (both with 0.1% DEA), 25:75 v/v;flow-rate:1.2 ml min⁻¹] indicated that this material had an ee of 69.8%with the faster eluting single enantiomer [retention time 34.2 mins]being the minor component relative to the slower eluting singleenantiomer [retention time 50.9 mins].This material as a solution in DCM/MeOH 1:1 was treated with 4M HCl indioxane (0.5 mL), evaporated to dryness, then dried under vacuum toprovide the title compound.

Example 352(1S,3S,4S)-3-Hydroxy-4-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide dihydrochloride

(a) (1S,4R,5S)-4-Bromo-6-oxabicyclo[3.2.1]octan-7-one

(S)-Cyclohex-3-enecarboxylic acid (1.98 g, 15.7 mmol) ([α]_(D)=−92.7°(c=1, CHCl₃)=97.5% e.e., resolved by the method of Schwartz et al, J.Am. Chem. Soc., 100, 5199, (1978)) was reacted with trimethylsilylbromide (4.10 mL, 31.3 mmol), DMSO (2.23 mL, 31.3 mmol), andN,N-diisopropylethylamine (4.45 mL, 31.3 mmol) (by a modification of themethod of Iwata et al, Heterocycles., 31, 987 (1990)) to give a whitesolid, (2.91 g, 14.2 mmol, 90%);

¹H NMR δ (400 MHz; CDCl₃) 1.68 (1H, dddd), 1.86 (1H, d), 1.97-2.06 (1H,m), 2.20 (1H, dddd), 2.42 (1H, ddd), 2.50-2.57 (1H, m), 2.73 (1H, br s),4.16 (1H, dd), 4.92 (1H, d).

(b) (1S,3S,4R)-4-Bromo-3-hydroxycyclohexanecarboxylic amide

(1S,4R,5S)-4-Bromo-6-oxabicyclo[3.2.1]octan-7-one (352a) (2.88 g, 14.0mmol) was taken up in THF (27 mL) and treated with 0.880 ammonia (7.1mL) at 20° C. for 24 h with stirring. The solvent was then removed invacuo to give a white solid in quantitative yield; [α]_(D)=−55.4° (c=1,MeOH).

¹H NMR δ (400 MHz; CD₃OD) 1.64 (1H, dd), 1.74-1.82 (1H, m), 1.85-2.05(3H, m), 2.13-2.22 (1H, m), 2.37 (1H, tt), 3.53 (1H, dt), 4.55 (1H, bs).

(c) (1S,3S,4S)-4-Azido-3-hydroxy-cyclohexanecarboxylic acid amide

(1S,3S,4R)-4-Bromo-3-hydroxycyclohexanecarboxylic amide (352b) (3.11 g,14.0 mmol) was treated with sodium azide (1.82 g, 28.0 mmol) in DMF (140mL) at 60° C. for 16 h. The solvent was removed in vacuo and the residuepurified by flash column chromatography (silica gel, DCM:MeOH/NH₃ (2N)0-5%) to give the a white solid (1.30 g, 7.0 mmol, 50%); [α]_(D)=+17.7°(c=1, MeOH).

¹H NMR δ(400 Mz; CD₃OD) 1:30 (1H, dq), 1.44-1.57 (2H, m), 1.82 (1H, dt),2.00-2.10 (2H, m), 2.30 (1H, tt), 3.16(1H, ddd), 3.41 (1H, ddd).

(d) (1S,3S,4S)-4-amino-3-hydroxy-cyclohexanecarboxylic acid amide

To (1S,3S,4S)-4-azido-3-hydroxy-cyclohexanecarboxylic acid amide (352c)(760 mg, 4.13 mmol) in MeOH (30 mL) was added Pd/C (10%, 500 mg), andthe mixture hydrogenated under atmospheric pressure for 18 h. Oncompletion of reaction the mixture was filtered through Celite®, thefilter pad washed with MeOH, and the combined organic solutionsconcentrated in vacuo to give a white solid in quantitative yield;

¹H NMR δ (400 MHz; CD₃OD) 1.22 (1H, dq). 1.4-1.54 (2H, m), 1.76-1.83(1H, m), 1.89-1.96 (1H, m), 1.99-2.07 (1H, m), 2.32 (1H, tt), 2.47 (1H,dt), 3.19 (1H, dt).

(e) ((1S,2S,4S)-4-Carbamoyl-2-hydroxy-cyclohexyl)-carbamic acidtert-butyl ester

The amide (352d) (653 mg, 4.13 mmol) was treated withdi-tert-butyl-dicarbonate (1.08 g, 4.95 mmol) in dioxane (30 mL), andMeOH (50 mL) for 16 h. The solvent was then removed in vacuo and theresidue purified by flash column chromatography (silica gel, DCM:MeOH5-10%) to give a white solid (890 mg, 3.45 mmol, 84%); [α]_(D)=+17.0°(c=1, MeOH).

¹H NMR δ (400 MHz; CD₃OD) 1.21-1.31 (1H, m), 1.44 (9H, s), 1.43-1.56(2H, m), 1.81 (1H, bd), 1.98 (1H, bd), 2.09 (1H, bd), 2.29 (1H, tt),3.21 (1H, dt), 3.34 (1H, dt

(f)[(1S,2S,4S)-2-Hydroxy-4-(6-methoxy-[1,5]naphthyridin-4-ylcarbamoyl)-cyclohexyl]-carbamicacid tert-butyl ester

The carbamate (352e) (400 mg, 1.55 mmol) was reacted with the triflateester (1b) (477 mg, 1.55 mmol) by the procedure of Example (350f) togive a white solid (400 mg, 0.960 mmol, 62%);

¹H NMR δ (400 MHz; CD₃OD) 1.34-1.50 (1H, m), 1.46 (9H, s), 1.60-1.71(2H, m), 2.04-2.12 (2H, m), 2.32-2.38 (1H, m), 2.75 (1H, bt), 3.27-3.34(1H, m), 3.42-3.51 (1H, m), 4.16 (3H, s), 7.26 (1H, d), 8.18 (1H, d),8.49 (1H, d), 8.61 (1H, d); MS (+ve ion electrospray) m/z 417 (MH⁺,100%).

(g) (1S,3S,4S)-4-Amino-3-hydroxy-cyclohexanecarboxylic acid(6-methoxy-[1,5]naphthyridin-4-yl)-amide

The amide (352f) (691 mg, 1.66 mmol) in DCM (30 mL) was treated withtrifluoroacetic acid (20 mL). After 45 min the solvent was removed invacuo and the residue purified by flash column chromatography (silicagel, DCM:MeOH/NH₃ (2M) 5%) to give a white solid (376 mg, 1.19 mmol,72%); [α]_(D)=+0.50 (c=1, MeOH).

¹H NMR δ (400 MHz; CD₃OD) 1.33-1.46 (1H, m), 1.59-1.71 (2H, m),2.00-2.12 (2H, m), 2.27-2.32 (1H, m), 2.57-2.65 (1H, m), 2.76-2.84 (1H,m), 3.32-3.40 (1H, m), 4.17 (3H, s), 7.27 (1H, d), 8.19 (1H, d), 8.50(1H, d), 8.61 (1H, d); MS (+ve ion electrospray) m/z 317 (MH⁺, 100%).

(h) Title Compound

This was prepared following the method of Example (351h) on a 0.657 mmolscale from amide (352 g), and aldehyde (301d), to give the free base ofthe title compound in 53% yield;

¹H NMR δ (400 MHz; CDCl₃) 1.29-1.41 (1H, m), 1.6-1.8 (2H, m), 2.15 (1H,bd), 2.24 (1H, bd), 2.41 (1H, bd), 2.49-2.63 (2H, m), 3.40, 3.44 (2H,ABq), 3.58 (1H, m), 3.85 (1H, d), 4.05 (1H, d), 4.10 (3H, s), 4.5 (1H,b) 6.91 (1H, d), 7.13 (1H, d), 7.54 (1H, d), 8.20 (1H, d), 8.48 (1H, d),8.67 (1H, d), 9.49 (1H, s); MS (+ve ion electrospray) m/z 495 (MH⁺,100%).

Analytical HPLC [Chiralpak AD 250 mm×4.6 mm i.d.; 10 micron particlesize; eluent; n-hexane-ethanol (both with 0.1% DEA), 25:75 v/v;flow-rate:1.2 ml min⁻¹] indicated that this material had an ee of 89.6%with the faster eluting single enantiomer [retention time 33.5 mins]being the major component relative to the slower eluting singleenantiomer [retention time 50.9 mins].

This material as a solution in DCM/MeOH 1:1 was treated with 4M HCl indioxane (0.5 mL), evaporated to dryness, then dried under vacuum toprovide the title compound.

Example 353(1S,3S,4S)-4-[(7-Chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)-amino]-3-hydroxy-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide and(1R,3R,4R)-4-[(7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)-amino]-3-hydroxy-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide dihydrochloride

(a) Title Compound

A mixture of the carboxaldehyde (306e)(54 mg) and racemic amine (350 g)(74 mg) in chloroform (3 ml)/methanol (3 ml) with 3A molecular sieveswas refluxed 18 hours, cooled and treated with sodiumtriacetoxyborohydride (149 mg). After stirring overnight, the mixturewas diluted with dichloromethane (50 ml) and washed with aqueous NaHCO₃.The aqueous fraction was re-extracted with 10% methanol indichloromethane and the combined organic fractions dried (MgSO₄) andevaporated. Chromatography of the residue (CH₂Cl₂:MeOH 90:10) gave thefree base of the title compound (23 mg).

¹H NMR δ(DMSO) 1.11-1.56 (3H, m), 1.91-2.32 (4H, m), 2.7-2.9 (1H, m),3.55 (2H, s), 3.7-4.1 (3H, m), 4.12 (3H, s), 4.75 (1H,s), 7.3 (1H, d),7.9 (1H, s), 8.2 (1H, d), 8.4 (1H, d), 8.7 (1H, d), 9.7 (1H, s), 11.10(1H, s).

This material as a solution in dichloromethane:methanol 1:1 was treatedwith 4M HCl in dioxane (0.10 ml) and evaporated to dryness. The solidwas triturated under ether, filtered and dried under vacuum to providethe title compound (25 mg).

MS (+ve ion electrospray) m/z 529 (MH+, 100%).

Example 354(1S,3S,4S)-3-Hydroxy-4-[(7-fluoro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide dihydrochloride and(1R,3R,4R)-3-Hydroxy-4-[(7-fluoro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide dihydrochloride

A mixture of the carboxaldehyde (308f) (41 mg) and the amine (350 g) (60mg) in chloroform (1.5 ml)/methanol (1.5 ml) with 3A molecular sieveswas refluxed 18 hours, cooled and treated with sodiumtriacetoxyborohydride (143 mg). After stirring for 5 hours at roomtemp., the mixture was filtered, diluted with chloroform (20 ml) andwashed with aqueous NaHCO₃. The aqueous fraction was re-extracted with10% ethanol in chloroform (2×10 ml) and the combined organic fractionsdried (MgSO₄) and evaporated. Chromatography of the residue on silicagel (CHCl₃/MeOH/NH₄OH 95:5:0.5) gave the free base of the title compound(80 mg).

¹H NMR δ(CDCl₃) 1.3-1.5 (1H, m), 1.6-1.8 (2H, m),2.13 (1H, broad d),2.26 (1H, broad d), 2.41 (1H, broad d), 2.45-2.6 (2H, m), 3.44 (2H, s),3.55-3.65 (1H, m), 3.93 (1H, d), 4.05-4.15 (4H, m including 3H, s at δ4.09), 7.14 (1H, d), 7.32 (1H, d), 8.21 (1H, d), 8.48 (1H, d), 8.68 (1H,d), 9.48 (1H, s)

This material as a solution in chloroform/ethanol 1:1 was treated with1M HCl in ether (0.4 ml) and evaporated to dryness to provide the titlecompound (89 mg).

MS (+ve ion electrospray) m/z 513 (MH⁺, 100%)

Example 355(1S,3S,4S)-3-Hydroxy-4-[(2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazin-7-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide dihydrochloride and(1R,3R,4R)-3-Hydroxy-4-[(2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazin-7-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide dihydrochloride

A mixture of the carboxaldehyde (309i) (34 mg) and the amine (350 g) (60mg) in chloroform (1.5 ml)/methanol (1.5 ml) with 3A molecular sieveswas refluxed 18 hours, cooled and treated with sodiumtriacetoxyborohydride (143 mg). After stirring for 5 hours at room temp.and 2 hours at 45° C., the mixture was filtered, diluted with chloroform(20 ml) and washed with aqueous NaHCO₃. The aqueous fraction wasre-extracted with 10% ethanol in chloroform (3×10 ml) and the combinedorganic fractions dried (MgSO₄) and evaporated. Chromatography of theresidue on silica gel (CHCl₃/MeOH/NH₄OH 95:5:0.5) gave the free base ofthe title compound (45 mg).

¹H NMR δ(CDCl₃/CD₃OD) 1.2-1.4 (1H, m), 1.5-1.8 (2H, m), 2.1-2.3 (2H, m),2.3-2.6 (2H, m), 2.6-2.8 (1H, m), 3.4-3.6 (1H, m), 3.80 (1H, d), 3.94(1H, d), 4.16 (3H, s), 4.67 (2H, s), 6.91 (1H, s), 7.22 (1H, d), 8.13(1H, s), 8.20 (1H, d), 8.50 (1H, d), 8.62 (1H, d) This material as asolution in chloroform/ethanol 1:1 was treated with 1M HCl in ether (0.2ml) and evaporated to dryness to provide the title compound (50 mg).

MS (+ve ion electrospray) m/z 479 (MH⁺, 100%)

Example 356(1S,3S,4S)-3-Hydroxy-4-[(2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]thiazin-7-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide dihydrochloride and(1R,3R,4R)-3-Hydroxy-4-[(2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]thiazin-7-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide dihydrochloride

A mixture of the carboxaldehyde (302 g) (20 mg) and the amine (350 g)(33 mg) in DMF (1.5 ml)/methanol (1.5 ml)/acetic acid (0.15 ml) wasrefluxed 3 hours, cooled and treated with sodium cyanoborohydride (13mg). After stirring for 18 hours at room temp., the mixture was dilutedwith 10% methanol in chloroform (20 ml), filtered and evaporated todryness. The residue was treated with aqueous NaHCO₃ (10 ml), extractedwith 10% methanol in chloroform (4×10 ml) and the combined organicfractions dried (MgSO₄) and evaporated. Chromatography of the residue onsilica gel (CHCl₃/MeOH/NH₄OH 93:7:0.7) gave the free base of the titlecompound (25 mg).

This material as a solution in chloroform was treated with 1M HCl inether (0.12 ml) and evaporated to dryness to provide the title compound(24 mg).

Example 357(1S,3S,4S)-3-Hydroxy-4-[(6-oxo-6,7-dihydro-5H-8-thia-1,2,5-triaza-naphthalen-3-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide dihydrochloride and(1R,3R,4R)-3-hydroxy-4-[6-oxo-6,7-dihydro-5H-8-thia-1,2,5-triaza-naphthalen-3-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide dihydrochloride

A mixture of the carboxaldehyde (312d) (55 mg) and the amine (350 g) (40mg) in DMF (1.5 ml)/methanol (1.5 ml)/acetic acid (0.15 ml) was refluxed8 hours with 3A molecular sieves, cooled and treated with sodiumcyanoborohydride (24 mg). After stirring for 18 hours at room temp., themixture was diluted with 10% methanol in chloroform, filtered andevaporated to dryness. The residue was treated with aqueous Na₂CO₃,extracted with 10% methanol in chloroform (4×) and the combined organicfractions dried (Na₂SO₄) and evaporated. Chromatography of the residueon silica gel (CHCl₃ then 2-10% methanol-dichloromethane) gave the freebase of the title compound (32 mg).

¹H NMR δ(CDCl₃/CD₃OD) 1.2-1.4 (1H, m), 1.5-1.8 (2H, m), 2.1-2.6 (4H, m),2.6-2.8 (1H, m), 3.5 (1H, m), 3.7 (2H, s), 4.1 (2H, q), 4.16 (3H, s),7.05 (1H, s), 7.22 (1H, d), 8.20 (1H, d), 8.50 (1H, d), 8.62 (1H, d). MS(+ve ion electrospray) m/z 496 (MH⁺)

This material as a solution in chloroform/methanol was treated with 4MHCl in dioxan, evaporated to dryness and triturated with ether, toprovide the title compound (38 mg).

Example 358(1S,3S,4S)-3-Hydroxy-4-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)-amino]-cyclohexanecarboxylicacid (6,8-difluoro-quinolin-4-yl)amide dihydrochloride and(1R,3R,4R)-3-Hydroxy-4-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)-amino]-cyclohexanecarboxylicacid (6,8-difluoroquinolin-4-yl)-amide dihydrochloride

(a) 4-Bromo-6,8-difluoro-quinoline

This was prepared from 4-hydroxy-6,8-difluoro-quinoline by heating withphosphorus tribromide in dimethylformamide.

(b) (1R,3S,4S)- and(1S,3R,4R)-4-(6,8-Difluoro-quinolin-4-ylcarbamoyl)-2-hydroxy-cyclohexyl]-carbamicacid tert butyl ester

A mixture of the amide (350e) (0.34 g), cesium carbonate (0.52 g),tris(dibenzylideneacetone)dipalladium(0) (24.5 mg), andrac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (49 mg) in dry dioxan(15 ml) under argon, was sonicated for 10 minutes, the bromo-quinoline(358a) (0.32 g) was added, and the mixture was stirred and heated at 95°C. for 12 hours, under argon. The mixture was cooled, filtered, and thefiltrate evaporated and chromatographed on silica gel, eluting withchloroform, then (2-5%) methanol-dichloromethane, to afford a solid(0.34 g).

MS (+ve ion electrospray) m/z 422 (MH+).

(c) (1S,3S,4S)- and (1R,3R,4R-4-Amino-3-hydroxy-cyclohexanecarboxylicacid (6,8-difluoro-quinolin-4-yl)-amide

The carbamate (358b) (0.34 g) in dichloromethane (20 ml) was treatedwith trifluoroacetic acid (20 ml) for 2 hours and evaporated. Sodiumcarbonate solution was added and the solution was extracted (5×) with10% methanol-chloroform, dried (sodium sulfate) and evaporated to give awhite solid (0.245 g).

MS (+ve ion electrospray) m/z 322 (MH+).

(d) Title Compound

A mixture of carboxaldehyde (301d) (43 mg) and amine (358c) (72 mg) inanhydrous dimethylformamide (2 ml), methanol (2 ml) and acetic acid (0.2ml) was heated over 3A molecular sieves at 80° C. for 2 h. Aftercooling, sodium cyanoborohydride (42 mg) was added and the mixture wasstirred at room temperature overnight. The mixture was filtered, andevaporated and the residue basified with sodium carbonate and extractedseveral times with 10% methanol/chloroform and the combined organicfractions were dried and evaporated. Chromatography on silica gel (2-10%methanol/dichloromethane) gave the free base of the title compound (50mg).

¹H NMR δ(CDCl₃/CD₃OD) 1.2-1.8 (3H, m), 2.03 (1H, m), 2.25 (2H, m), 2.5(1H, m), 2.78 (1H, m), 3.49 (3H, m), 3.78 (1H, d), 3.95 (1H, d), 6.96(1H, d), 7.35 (1H, m), 7.65 (1H, d), 7.8 (1H, m), 8.28 (1H, d), 8.75(1H, d) MS (+ve ion electrospray) m/z 500 (MH⁺)

The free base in chloroform/methanol (1:1) was treated with 4M HCl indioxan (0.2 ml) and evaporated to dryness. The solid was triturated withether, filtered and dried in vacuo, to provide title compound (59 mg).

Example 359(1R,3R,4R)-3-Hydroxy-4-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide dihydrochloride

The amine (351 g) (0.47 nmol) under argon in MeOH (15 mL) and DMF (15mL) was treated with the carboxaldehyde (305e) (0.47 mmol), and 3Amolecular sieves (1 g), followed by AcOH (1.5 mL).(Polystyryhmethyl)trimethylammonium cyanoborohydride (0.940 mmol) wasadded after 20 min. Once the reaction had gone to completion the resinwas removed by filtration, and the solvent removed in vacuo. The residuewas purified by flash column chromatography (silica gel, DCM:MeOH/NH₃(2M) 0-12%) to give the free base of the title compound in 79% yield.

¹H NMR δ (CD₃OD/CDCl₃) 1.24-1.35 (1H, m), 1.58-1.74 (2H, m), 2.10-2.16(1H, m), 2.17-2.23 (1H, m), 2.32-3.38 (1H, m), 2.43-2.50 (1H, m), 2.62(1H, tt), 3.48-3.52 (1H, m), 3.75, 3.94 (2H, ABq), 4.14 (3H, s), 4.64(2H, s), 6.88 (1H, d), 7.20 (1H, d), 7.21 (1H, d), 8.21 (1H, d), 8.50(1H, d), 8.65 (1H, d); MS (+ve ion electrospray) m/z 479 (MH⁺, 100%).

This material as a solution in DCM/MeOH 1:1 was treated with 4M HCl indioxane (0.5 mL), evaporated to dryness, then dried under vacuum toprovide the title compound.

Example 360(1R,3R,4R)-3-Hydroxy-4-[(7-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide dihydrochloride

This was prepared by the method of Example (359) on a 0.449 mmol scalefrom amine (351 g) and aldehyde (310d), to give the free base of thetitle compound in 74% yield; ¹H NMR δ (CD₃OD/CDCl₃) 1.28-1.40 (1H, m),1.61-1.77 (2H, m), 2.12-2.18 (1H, m), 2.21-2.27 (1H, m), 2.25 (3H, s),2.37-2.43 (1H, m), 2.48-2.55 (1H, m), 2.62 (1H, tt), 3.45 (2H, s),3.52-3.58 (1H, m), 3.77, 3.97 (2H, ABq), 4.14 (3H, s), 7.18 (1H, d),7.40 (1H, s), 8.22 (1H, d), 8.50 (1H, d), 8.66 (1H, d); MS (+ve ionelectrospray) m/z 509 (MH⁺, 100%).This material as a solution in DCM/MeOH 1:1 was treated with 4M HCl indioxane (0.5 mL), evaporated to dryness, then dried under vacuum toprovide the title compound.

Example 361(1R,3R,4R)-3-Hydroxy-4-[(2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]thiazin-7-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide dihydrochloride

This was prepared by the method of Example (359) on a 0.470 mmol scalefrom amine (351 g) and aldehyde (302 g), to give the free base of thetitle compound in 79% yield ¹H NMR δ(400 MHz, CD₃OD/CDCl₃) 1.25-1.36(1H, m), 1.59-1.72 (2H, m), 2.11-2.17 (1H, m), 2.18-2.24 (1H, m),2.34-2.40 (1H, m), 2.43-2.50 (1H, m), 2.63 (1H, tt), 3.46 (2H, m),3.46-3.52 (1H, m), 3.83, 3.97 (2H, ABq), 4.15 (3H, s), 6.91 (1H, s),7.22 (1H, d), 8.20 (1H, d), 8.36 (1H, s), 8.50 (1H, d), 8.63 (1H, d); MS(+ve ion electrospray) m/z 495 (MH⁺, 100%).This material as a solution in DCM/MeOH 1:1 was treated with 4M HCl indioxane (0.5 mL), evaporated to dryness, then dried under vacuum toprovide the title compound.

Example 362(1S,3S,4S)-3-Hydroxy-4-[(7-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide dihydrochloride

This was prepared by the method of Example (359) on a 0.432 mmol scalefrom amine (352 g), and aldehyde (310d), to give the free base of thetitle compound in 85% yield; ¹H NMR δ (400 MHz; CD₃OD/CDCl₃) 1.28-1.37(1H, m), 1.59-1.76 (2H, m), 2.13 (1H, bd), 2.20-2.24 (1H, m), 2.25 (3H,s), 2.38 (1H, bd), 2.51 (1H, dt), 2.65 (1H, tt), 3.45 (2H, s), 3.52-3.58(1H, m), 3.75, 3.95 (2H, ABq), 4.15 (3H, s), 7.21 (1H, d), 7.42 (1H, s),8.20 (1H, d), 8.50 (1H, d), 8.64 (1H, d); MS (+ve ion electrospray) m/z509 (MH⁺, 100%).This material as a solution in DCM/MeOH 1:1 was treated with 4M HCl indioxane (0.5 mL), evaporated to dryness, then dried under vacuum toprovide the title compound.

Example 363(1S,3S,4S)-3-Hydroxy-4-[(2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]thiazin-7-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide dihydrochloride

This was prepared by the method of Example (359) on a 0.463 mmol scalefrom amine (352 g) and aldehyde (302 g), to give the free base of thetitle compound in 52% yield; ¹H NMR δ (400 MHz; CD₃OD/CDCl₃) 1.25-1.36(1H, m), 1.59-1.74 (2H, m), 2.15 (1H, bd), 2.18-2.24 (1H, m), 2.38 (1H,bd), 2.47 (1H, dt), 2.65 (1H, tt), 3.45 (2H, m), 3.46-3.53 (1H, m),3.83, 3.97 (2H, ABq), 4.15 (3H, s), 6.92 (1H, s), 7.22 (1H, d), 8.19(1H, d), 8.36 (1H, s), 8.50 (1H, d), 8.63 (1H, d); MS (+ve ionelectrospray) m/z 495 (MH⁺, 100%).This material as a solution in DCM/MeOH 1:1 was treated with 4M HCl indioxane (0.5 mL), evaporated to dryness, then dried under vacuum toprovide the title compound.The following compounds were made by the method of Example (350h).

Method of salt synthesis B Example (aldehyde) StereochemistryDihydrochloride X R 380 (4c) 1S,3S,4S/1R,3R,4R B N

381 (13e) IS,3S,4S/1R,3R,4R B N

382 (20e) 1S,3S,4S/1R,3R,4R B N

383 a 1S,3S,4S/1R,3R,4R B CH

a prepared from 4-bromo-6-methoxyquinoline (itself prepared from6-methoxy-quinolin-4-ol by the method of Example 391a) by the method ofExample 350(f-h)

Example 3901-Hydroxy-t-4-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)-amino-r-cyclohexanecarboxylicacid (8-fluoro-6-methoxy-quinolin-4-yl)-amide dihydrochloride

(a)[4-(8-Fluoro-6-methoxy-quinolin-4-ylcarbamoyl)-r-4-hydroxy-c-cyclohexyl]-carbamicacid tert-butyl ester

A mixture of amide (300c) (1.46 g, 5.66 mmol) and cesium carbonate (2.66g, 8.18 mmol) in 1,4-dioxan was deoxygenated by bubbling in a stream ofargon for 5 mins. Tris(dibenzylideneacetone)dipalladium(0) (0.125 g,0.13 mmol) and rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.25 g,0.40 mmol) were added and deoxygenation continued for 2 mins. Themixture was the sonicated for 15 mins. Triflate ester (10b) (2.2 g, 6.77mmol) was added and the mixture heated at 105° C. overnight. Thereaction mixture was filtered and the filtered solids extracted with hotchloroform/methanol. The combined organics were evaporated and the crudeproduct purified on silica gel eluting with 5% methanol/dichloromethaneto give a solid (1.29 g, 53%). MS (+ve ion electrospray) m/z 434 (MH+).

(b) t-4-Amino-1-hydroxy-r-cyclohexanecarboxylic acid(8-fluoro-6-methoxy-quinolin-4-yl)-amide

The carbamate (390a) (1.28 g, 2.96 mmol) in dichloromethane (20 ml) andtrifluoroacetic acid (10 ml) was stirred for 2 hours at room temperatureand then evaporated. The residue was basified with sodium carbonate andice-water, the precipitate washed with water and dried, to give a solid(0.97 g, 98%).

(c) Title Compound

The amine (390b) (0.17 g, 0.51 mmol) and carboxaldehyde (301d) (0.099 g,0.51 mmol) in methanol (5 ml) and chloroform (5 ml) were stirred at 65°C. with 3A sieves for 18 hours. The mixture was allowed to cool andsodium triacetoxyborohydride (0.50 g, 2.36 mmol) was added. After themixture had been stirred for 3 days it was filtered and evaporated. Theresidue was neutralised with sodium carbonate solution and extractedwith 10% methanol in chloroform. The extracts were dried and evaporatedand the crude product purified on silica gel eluting with 0-10% methanolin dichloromethane to give the free base of the title compound (0.224 g,91%).

¹H NMR δ(CDCl₃/CD₃OD) 1.6-1.8 (2H, m), 1.8-2.2 (7H, m), 2.72 (1H, m),3.4 (2H, d), 3.5 (2H, s), 3.95 (2H, s), 3.97 (3H, s), 6.92 (2H, m), 7.15(1H, d), 7.65 (1H, d), 8.35 (1H, d), 8.7 (1H, d).

Addition of 4M hydrochloric acid in dioxan and trituration of theprecipitate with ether effected conversion to the title compound.

MS (+ve ion electrospray) m/z 483 (MH+)

Example 3911-Hydroxy-t-4-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)-amino-r-cyclohexanecarboxylicacid (6-methoxy-quinolin-4-yl)-amide dihydrochloride

(a) 4-Bromo-6-methoxy-quinoline

This was prepared by heating 6-methoxy-quinolin-4-ol (1 g) andphosphorus oxybromide (5 g) in chloroform (40 ml) under reflux for 18hours. The mixture was cooled, basified with sodium bicarbonate,extracted with 5% methanol-chloroform, and dried (sodium sulfate). Theproduct was chromatographed on silica gel (2-5%methanol-dichloromethane) to afford a solid (0.68 g).

MS (+ve ion electrospray) m/z 238/240 (MH+)

Alternatively, this material was prepared in approximately 90% yield bytreatment with one equivalent of phosphorous tribromide inN,N-dimethylformamide.

(b)[4-(6-Methoxy-quinolin-4-ylcarbamoyl)-r-4-hydroxy-c-cyclohexyl]-carbamicacid tert-butyl ester

A mixture of amide (300c) (0.84 g) and cesium carbonate (1.20) in1,4-dioxan (40 ml) was deoxygenated by bubbling in a stream of argon for5 mins. Tris(dibenzylideneacetone)dipalladium(0) (60 mg) andrac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (120 mg) were added anddeoxygenation continued for 2 mins. The mixture was the sonicated for 10mins. The bromide (391a) (0.8 g) was added and the mixture heated at103° C. overnight. The reaction mixture was filtered and the filteredsolids extracted with hot chloroform/methanol. The combined organicswere evaporated and the crude product purified on silica gel elutingwith chloroform then 2% methanol/dichloromethane to give a solid (1.27g).

MS (+ve ion electrospray) m/z 416 (MH+).

(c) t-4-Amino-1-hydroxy-r-cyclohexanecarboxylic acid(6-methoxy-quinolin-4-yl)-amide

The carbamate (391b) (1.43 g) in dichloromethane (50 ml) andtrifluoroacetic acid (50 ml) was stirred for 2 hours at room temperatureand then evaporated. The residue was basified with sodium carbonate andice-water, the precipitate washed with water and dried, to give a solid(0.8 g).

MS (+ve ion electrospray) m/z 316 (MH+).

(d) Title Compound

The amine (391c) (0.162 g) and carboxaldehyde (301d) (0.1 g) in methanol(8 ml) and chloroform (8 ml) were stirred at 65° C. with 3A sieves for18 hours. The mixture was allowed to cool and sodiumtriacetoxyborohydride (0.50 g) was added. After the mixture had beenstirred for 2 days it was filtered and evaporated. The residue wasneutralised with sodium carbonate solution and extracted with 5%methanol in chloroform. The extracts were dried and evaporated and thecrude product purified on silica gel eluting with chloroform then 2-10%methanol in dichloromethane to give the free base of the title compound(0.2 g).

¹H NMR δ(CDCl₃/CD₃OD) 1.6-1.8 (2H, m), 1.8-2.2 (6H, m), 2.62 (1H, m),3.4 (2H, d), 3.5 (2H, s), 3.87 (2H, s), 4.0 (3H, s), 6.98 (2H, m), 7.2(1H, d), 7.42 (1H, dd), 7.65 (1H, d), 7.95 (1H, d), 8.25 (1H, d), 8.62(1H, d).

Addition of 4M hydrochloric acid in dioxan and trituration of theprecipitate with ether effected conversion to the title compound.

MS (+ve ion electrospray) m/z 494 (MH+)

Example 3921-Hydroxy-t-4-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)-amino-r-cyclohexanecarboxylicacid (6,8-difluoro-quinolin-4-yl)-amide dihydrochloride

(a) 1,1,1-Trifluoro-methanesulfonic acid 6,8-difluoro-quinolin-4-ylester

Sodium hydride 60% dispersion in oil (0.062 g, 1.55 mmol) was washedwith hexane and suspended in DMF. After cooling to 0° C.6,8-difluoro-quinolin-4-ol (0.20 g, 1.1 mmol) was added and the mixturestirred at 0° C. for 15 mins. N-Phenyltrifluoromethane sulfonimide (0.47g, 1.3 mmol) was added and the mixture allowed to warm to roomtemperature and stirred overnight. The solvent was evaporated and theresidue partitioned between ethyl acetate and water. The aqueous phasewas extracted with ethyl acetate and the combined organics driedevaporated and chromatographed on silica gel eluting withdichloromethane to give the triflate (0.318 g, 92%)

MS (+ve ion electrospray) m/z 314 (MH+).

(b)[4-(6,8-Difluoro-quinolin-4-ylcarbamoyl)-r-4-hydroxy-c-cyclohexyl]-carbamicacid tert-butyl ester

The carboxamide (300c) (0.25 g, 0.97 mmol) and the triflate ester (392a)(0.318 g, 1.0 mmol) were reacted by the method of Example(391b) exceptthat the mixture was heated at 100-105° C. to give the carbamate (0.165g, 40%).

MS (+ve ion electrospray) m/z 422 (MH+).

(c) t-4-Amino-1-hydroxy-r-cyclohexanecarboxylic acid(6,8-difluoro-quinolin-4-yl)-amide

The carbamate was deprotected with trifluoroacetic acid by the method ofExample (391c).

(d) Title Compound

The amine (392c) (0.067 g, 0.21 mmol) was reacted with carboxaldehyde(301d) (0.049 g, 0.25 mmol) in methanol (3 ml) and chloroform (3 ml) inthe presence of 3A sieves at 65° C. overnight. The mixture was allowedto cool and further chloroform added (5 ml) to give a clear solution.Sodium triacetoxyborohydride (0.4 g) was added and the mixture stirredat room temperature for 48 hours. After decanting from the sieves themixture was evaporated, treated with sodium carbonate solution andextracted with 10% methanol in dichloromethane. The extracts were dried,evaporated and chromatographed on silica gel eluting with 2-10% methanolin dichloromethane to give the free base of the title compound (0.076 g,73%).

MS (+ve ion electrospray) m/z 500 (MH+).

¹H NMR δ(CDCl₃/CD₃OD) 1.55-1.7 (2H, m), 1.85-2.2 (6H, m), 2.68 (1H, m),3.5 (2H, s), 3.87 (2H, s), 6.92 (1H, d), 7.25-7.4 (2H, m), 7.65 (1H, d),8.43 (1H, d), 8.81 (1H, d).

Addition of 4M hydrochloric acid in dioxan and trituration of theprecipitate with ether effected conversion to the title compound.

The following compounds were prepared by analogous methods.

Method of synthesis salt Example (aldehyde) B Dihydrochloride X R 400 a(19d) B F

421 a (13e) B F

422 b (304g) B H

423 b (19d) B H

424 b (305e) B H

425 c (301d) B OMe

426 a (306e) B F

a prepared by the method of Example (390) b prepared by the method ofExample (391) c prepared from 4-bromo-6,8-dimethoxy-quinoline by themethod of Example (391)

Example 4306-({4-hydroxy-4-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-cyclohexylamino}-methyl)-4H-pyrido[3,2-b][1,4]oxazin-3-one

(a) (4-Hydroxy-4-trimethylsilanyl-cyclohexyl)-carbamic acid tert-butylester

A solution of trimethylsilyl acetylene at −78° C.(4.14 g, 0.042 mol) inTHF (60 mL) was treated with n-butyl lithium (29 mL, 0.042 mol; 1.6 Msolution in THF). The resulting mixture was stirred at −78° C. for 15min. A solution of N-4-Boc-aminocyclohexanone (3 g, 0.014 mol; Astatech,Inc) in THF (120 mL) was added dropwise over a period of 30 min. Theresulting mixture was stirred at −78° C. for 1 h and then allowed toslowly warm up to room temperature over 1 h. The reaction was quenchedwith a saturated solution of ammonium chloride and diluted with EtOAcand washed with saturated aqueous NaHCO₃ solution, H₂O, and saturatedaqueous NaCl solution. The organic layer was dried over MgSO₄ andconcentrated to yield an off-white foam (4.38 g, 100%).

MS (+ve ion electrospray) m/z 312 (M+H)⁺.

(b) (4-Ethynyl-4-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester

A solution of the carbamate (430a) (4.38 g, 0.014 mol) in MeOH (50 mL)was treated with K₂CO₃ (5.83 g, 0.42 mol) and stirred at roomtemperature for 3 h. The solvent was removed in vacuo and the residuewas partitioned between EtOAc and aqueous NaCl, and the organic layerwas dried (MgSO₄) and concentrated to yield an oil (2.7 g, 89%).

MS (+ve ion electrospray) m/z 240 (M+H)⁺.

(c)[4-Hydroxy-4-(6-methoxy-[1,5]naphthyridin-4-ylethynyl)-cyclohexyl]-carbamicacid tert-butyl ester

A solution of carbamate (430b) (2.7 g, 0.011 mol) and the triflate ester(1b) (3.13 g, 0.01 mol) in a 1:1 mixture of triethylamine and DMF (10 mLtotal volume) was treated with (Ph₃P)₂PdCl₂ (0.3 g; 4% mol) and CuI(0.24 g, 8% mol). The resulting mixture was heated at 70° C. for 24 h.The solvent was removed under reduced pressure and the residue waspartitioned between CH₂Cl₂ and aqueous NaCl, and the organic layer wasdried (MgSO₄), and concentrated in vacuo. The resulting oil was purifiedby flash column chromatography on silica gel (gradient: 20-50%EtOAc/hexane) to afford an oil (2.24 g, 50%).

MS (+ve ion electrospray) m/z 398 (M+H)⁺.

d){4-Hydroxy-4-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-cyclohexyl}-carbamicacid tert-butyl ester

A solution of carbamate (430c) (0.8 g, 2 mmol) in MeOH (10 mL) wastreated with 10% palladium on carbon (catalytic) and hydrogenated in aParr bottle for 6 h at 40 psi. The solution was filtered through a plugof celite®, and the filter pad was washed with MeOH. The filtrate wasconcentrated to yield a yellow oil (0.7 g, 80%). The product was usedwithout further purification.

MS (+ve ion electrospray) m/z 402 (M+H)⁺. NMR analysis indicated thatthe compound was a 5:1 mixture of isomers. The isomeric mixture was notfurther characterized and was carried on through the remaining steps.

(e) 4-Amino-1-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-cyclohexanol

A solution of carbamate (430d) (0.4 g, 1 mmol) in CH₂Cl₂ (10 mL) wastreated with trifluoroacetic acid (0.15 mL, 2 mmol). The solution wasallowed to stir for 1 h at room temperature and then concentrated underreduced pressure. MeOH was added and the solution was again concentratedto remove any excess TFA. The remaining solid was dissolved in MeOH (5mL) and treated with MP-Carbonate resin (1.00 g, 2.87 mmol; ArgonautTechnologies, Inc.). The solution was then filtered and concentrated toyield a brown oil (0.3 g, 70%). The product was used without furtherpurification.

MS (+ve ion electrospray) m/z 302 (M+H)⁺.

(f) Title Compound

The amine (430e) (0.169 g, 0.561 mmol) was added to a solution of thecarboxaldehyde (305e) (0.100 g, 0.561 mmol) dissolved in DMF (3 mL),MeOH (2 mL) and acetic acid (0.2 mL). 3Å molecular sieves were thenadded to the reaction mixture and the solution was allowed to stir at80° C. for 40 h. The solution was cooled to 0° C. and sodium borohydride(0.042 g, 1.12 mmol) was added. The reaction was stirred at ambienttemperature for 4 h. The reaction mixture was partitioned between ethylacetate and water. The organic layer was washed with water (2×) andbrine, dried (Na₂SO₄) and concentrated to yield a yellow oil. Theproduct was purified using flash column chromatography on silica gel(90:10:1 CHCl₃/MeOH/NH₄OH) to yield a yellow solid (0.025 g, 11%).

MS (+ve ion electrospray) m/z 464 (M+H)+. ¹H NMR (400 MHz, CDCl₃) δ 8.72(d, J=4.5 Hz, 1H), 8.18 (d, J=9.0 Hz, 1H), 7.40 (d, J=4.5 Hz, 1H), 7.20(d, J=9.0 Hz, 1H), 7.10 (d, J=9.0 Hz, 1H), 6.8 (d, J=9.0 Hz, 1H),4.60(s, 2H), 4.04 (s, 3H), 3.75 (s, 2H), 3.25 (m, 2H), 2.55 (m, 1H),1.91 (br m, 6H); 1.69 (m, 2H); 1.45 (m, 2H).

Biological Activity

The MIC (μg/ml) of test compounds against various organisms wasdetermined: S. aureus Oxford, S. aureus WCUH29, S. pneumoniae 1629, S.pneumoniae N1387, S. pueumoniae ERY 2, E. faecalis I, E. faecalis 7, H.influenzae Q1, H. influenzae NEMC1, M. catarrhalis 1502.

Examples 2-6, 8, 9, 12, 13, 19-21, 23, 28, 30, 31, 32, 34, 35, 101, 150,153, 154, 210-214, 300-305, 320-333, 380, 381, 390, 391, 400, 422, 423had MIC values ≦4 μg/ml versus all these organisms.

Examples 10, 11, 14-17, 22, 24, 26, 29, 102, 104, 155, 156, 215,334-336, 382 had MIC values ≦16 μg/ml versus all these organisms.

Examples 7, 18, 25, 27, 36, 100, 103, 105, 337 and 338 had MIC values≦64 μg/ml versus all these organisms.

The MIC (mg/ml) of further test compounds against an alternativeselection of organisms was determined:

S. aureus WCUH29, S. pneumoniae 1629, H. influenzae ATCC 51907, M.catarrhalis Ravisio.

Examples 306-310,312,314,350-363, 392, 421, 424-426,430 had MIC values≦4 μg/ml versus all these organisms.

Examples 311, 313, 340, 342, 343, 383 had MIC values ≦16 μg/ml versusall these organisms.

Examples 110, 111, 206, 341 had MIC values ≦16 μg/ml versus some1 ofthese organisms.

Other examples except 106 and 203 had MIC values ≦64 μg/ml versus atleast one of these organisms.

1. A compound of formula (I) or a pharmaceutically acceptable salt,solvate or N-oxide thereof:

wherein: one of Z¹, Z², and Z³ is N, one of the remainder of Z₁, Z₂, Z₃,Z₄ and Z₅ is CR^(1a) and the remainder are CH; R^(v) and R^(w) arehydrogen; R^(v) and R³; or R^(v) and R^(w) together are a bond; R¹ andR^(1a) are independently selected from hydrogen; hydroxy; (C₁₋₆) alkoxyoptionally substituted by (C₁₋₆)alkoxy, amino, piperidyl, guanidino oramidino any of which is optionally N-substituted by one or two(C₁₋₆)alkyl, (C₁₋₆)alkoxycarbonyl, formyl, (C₁₋₆)alkylcarbonyl, or(C₁₋₆)alkylsulphonyl groups, CONH2, hydroxy, (C₁₋₆)alkylthio,heterocyclylthio, heterocyclyloxy, arylthio, aryloxy,(C₁₋₆)alkyloxycarbonylthio, formylthio, (C₁₋₆)alkylcarbonylthio,(C₁₋₆)alkyloxycarbonyloxy, formyloxy, (C₁₋₆)alkylcarbonyloxy or(C₁₋₆)alkylsulphonyloxy; (C₁₋₆)alkoxy-substituted (C₁₋₆)alkyl; halogen;(C₁₋₆)alkyl; (C₁₋₆)alkylthio; trifluromethyl; nitro; azido;(C₁₋₆)alkoxycarbonyl; formyl; (C₁₋₆)alkylcarbonyl;(C₁₋₆)alkyloxycarbonyloxy, formyloxy, (C₁₋₆)alkylcarbonyloxy,(C₁₋₆)alkyloxycarbonylthio, formylthio; (C₁₋₆)alkylcarbonylthio;(C₁₋₆)alkylsulphonyl; (C₁₋₆)alkylsulphoxide; arylsulphonyl;arylsulphoxide or an amino, piperidyl, guanidino or amidino groupoptionally N-substituted by one or two (C₁₋₆)alkyl,(C₁₋₆)alkoxycarbonyl, formyl, (C₁₋₆)alkylcarbonyl or(C₁₋₆)alkylsulphonyl groups, or when Z¹ is CR^(1a), R¹ and R^(1a) maytogether represent (C₁₋₂)alkylenedioxy; or when Z⁵ is CR^(1a), R^(1a)may instead be cyano, hydroxymethyl or carboxy; R² is hydrogen, or(C₁₋₄)alkyl or (C₂₋₄)alkenyl optionally substituted with 1 to 3 groupsselected from: amino optionally substituted by one or two (C₁₋₄)alkylgroups; carboxy; (C₁₋₄)alkoxycarbonyl; (C₁₋₄)alkylcarbonyl;(C₂₋₄)alkenyloxycarbonyl; (C₂₋₄)alkenylcarbonyl; aminocarbonyl whereinthe amino group is optionally substituted by hydroxy, (C₁₋₄)alkyl,hydroxy(C₁₋₄)alkyl, aminocarbonyl(C₁₋₄)alkyl, (C₂₋₄)alkenyl,(C₁₋₄)alkylsulphonyl, trifluoromethylsulphonyl, (C₂₋₄)alkenylsulphonyl,(C₁₋₄)alkoxycarbonyl, (C₁₋₄)alkylcarbonyl, (C₂₋₄)alkenyloxycarbonyl or(C₂₋₄)alkenylcarbonyl; cyano; tetrazolyl; 2-oxo-oxazolidinyl optionallysubstituted by R¹⁰; 3-hydroxy-3-cyclobutene-1,2-dione-4-yl;2,4-thiazolidinedione-5-yl; tetrazol-5-ylaminocarbonyl;1,2,4-triazol-5-yl optionally substituted by R¹⁰;5-oxo-1,2,4-oxadiazol-3-yl; halogen; (C₁₋₄)alkylthio; trifluoromethyl;hydroxy optionally substituted by (C₁₋₄)alkyl, (C₂₋₄)alkenyl,(C₁₋₄)alkoxycarbonyl, (C₁₋₄)alkylcarbonyl, (C₂₋₄)alkenyloxycarbonyl,(C₂₋₄)alkenylcarbonyl; oxo; (C₁₋₄)alkylsulphonyl;(C₂₋₄)alkenylsulphonyl; or (C₁₋₄)aminosulphonyl wherein the amino groupis optionally substituted by (C₁₋₄)alkyl or (C₂₋₄)alkenyl; when R^(v)and R^(w) are a bond, R³ is in the 2-, 3- or 4-position and when R^(v)and R^(w) are not a bond, R³ is in the 1-, 2-, 3- or 4-position and R³is: hydrogen; carboxy; (C₁₋₆)alkoxycarbonyl; aminocarbonyl wherein theamino group is optionally substituted by hydroxy, (C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, aminocarbonyl(C₁₋₆)alkyl, (C₂₋₆)alkenyl,(C₁₋₆)alkylsulphonyl, trifluoromethylsulphonyl, (C₂₋₆)alkenylsulphonyl,(C₁₋₆)alkoxycarbonyl, (C₁₋₆)alkylcarbonyl, (C₂₋₆)alkenyloxycarbonyl or(C₂₋₆)alkenylcarbonyl and optionally further substituted by (C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, aminocarbonyl(C₁₋₆)alkyl or (C₂₋₆)alkenyl; cyano;tetrazolyl; 2-oxo-oxazolidinyl optionally substituted by R¹⁰;3-hydroxy-3-cyclobutene-1,2-dione-4-yl; 2,4-thiazolidinedione-5-yl;tetrazol-5-ylaminocarbonyl; 1,2,4-triazol-5-yl optionally substituted byR¹⁰; or 5-oxo-1,2,4-oxadiazol-3-yl; or (C₁₋₄)alkyl or ethenyl optionallysubstituted with any of the groups listed above for R³ and/or 0 to 2groups R¹² independently selected from: halogen; (C₁₋₆)alkylthio;trifluoromethyl; (C₁₋₆)alkoxycarbonyl; (C₁₋₆)alkylcarbonyl;(C₂₋₆)alkenyloxycarbonyl; (C₂₋₆)alkenylcarbonyl; hydroxy optionallysubstituted by (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₁₋₆)alkoxycarbonyl,(C₁₋₆)alkylcarbonyl, (C₂₋₆)alkenyloxycarbonyl, (C₂₋₆)alkenylcarbonyl oraminocarbonyl wherein the amino group is optionally substituted by(C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₁₋₆)alkylcarbonyl or(C₂₋₆)alkenylcarbonyl; amino optionally mono- or disubstituted by(C₁₋₆)alkoxycarbonyl, (C₁₋₆)alkylcarbonyl, (C₂₋₆)alkenyloxycarbonyl,(C₂₋₆)alkenylcarbonyl, (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₁₋₆)alkylsulphonyl,(C₂₋₆)alkenylsulphonyl or aminocarbonyl wherein the amino group isoptionally substituted by (C₁₋₆)alkyl or (C₂₋₆)alkenyl; aminocarbonylwherein the amino group is optionally substituted by (C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, aminocarbonyl(C₁₋₆)alkyl, (C₂₋₆)alkenyl,(C₁₋₆)alkoxycarbonyl, (C₁₋₆)alkylcarbonyl, (C₂₋₆)alkenyloxycarbonyl or(C₂₋₆)alkenylcarbonyl and optionally further substituted by (C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, aminocarbonyl(C₁₋₆)alkyl or (C₂₋₆)alkenyl; oxo;(C₁₋₆)alkylsulphonyl; (C₂₋₆)alkenylsulphonyl; or (C₁₋₆)aminosulphonylwherein the amino group is optionally substituted by (C₁₋₆)alkyl or(C₂₋₆)alkenyl; or hydroxy optionally substituted by (C₁₋₆)alkyl,(C₂₋₆)alkenyl, (C₁₋₆)alkoxycarbonyl, (C₁₋₆)alkylcarbonyl,(C₂₋₆)alkenyloxycarbonyl, (C₂₋₆)alkenylcarbonyl or aminocarbonyl whereinthe amino group is optionally substituted by (C₁₋₆)alkyl, (C₂₋₆)alkenyl,(C₁₋₆)alkylcarbonyl or (C₂₋₆)alkenylcarbonyl; or amino optionally mono-or disubstituted by (C₁₋₆)alkoxycarbonyl, (C₁₋₆)alkylcarbonyl,(C₂₋₆)alkenyloxycarbonyl, (C₂₋₆)alkenylcarbonyl, (C₁₋₆)alkyl,(C₂₋₆)alkenyl, (C₁₋₆)alkylsulphonyl, (C₂₋₆)alkenylsulphonyl oraminocarbonyl wherein the amino group is optionally substituted by(C₁₋₆)alkyl or (C₂₋₆)alkenyl; provided that when R³ is in the 4-positionit is not optionally substituted hydroxyl or amino; in addition when R³is disubstituted with a hydroxy or amino containing substituent and acarboxy containing substituent these may optionally together form acyclic ester or amide linkage, respectively; R¹⁰ is selected from(C₁₋₄)alkyl and (C₂₋₄)alkenyl either of which may be optionallysubstituted by a group R¹² as defined above; carboxy; aminocarbonylwherein the amino group is optionally substituted by hydroxy,(C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₁₋₆)alkylsulphonyl,trifluoromethylsulphonyl, (C₂₋₆)alkenylsulphonyl, (C₁₋₆)alkoxycarbonyl,(C₁₋₆)alkylcarbonyl, (C₂₋₆)alkenyloxycarbonyl or (C₂₋₆)alkenylcarbonyland optionally further substituted by (C₁₋₆)alkyl or (C₂₋₆)alkenyl;(C₁₋₆)alkylsulphonyl; trifluoromethylsulphonyl; (C₂₋₆)alkenylsulphonyl;(C₁₋₆)alkoxycarbonyl; (C₁₋₆)alkylcarbonyl; (C₂₋₆)alkenyloxycarbonyl; and(C₂₋₆)alkenylcarbonyl; R⁴ is a group —CH₂—R⁵ ₁ in which R⁵ ₁ is selectedfrom: (C₄₋₈)alkyl; hydroxy(C₄₋₈)alkyl; (C₁₋₄)alkoxy(C₄₋₈)alkyl;(C₁₋₄)alkanoyloxy(C₄₋₈)alkyl; (C₃₋₈)cycloalkyl(C₄₋₈)alkyl; hydroxy-,(C₁₋₆)alkoxy- or (C₁₋₆)alkanoyloxy-(C₃₋₈)cycloalkyl(C₄₋₈)alkyl;cyano(C₄₋₈)alkyl; (C₄₋₈)alkenyl; (C₄₋₈)alkynyl; tetrahydrofuryl; mono-or di-(C₁₋₆)alkylamino(C₄₋₈)alkyl; acylamino(C₄₋₈)alkyl; (C₁₋₆)alkyl- oracyl-aminocarbonyl(C₄₋₈)alkyl; mono- or di-(C₁₋₆)alkylamino(hydroxy)(C₄₋₈)alkyl; or R⁴ is a group —U—R⁵ ₂ where R⁵ ₂ is an optionallysubstituted bicyclic carbocyclic or heterocyclic ring system (A):

 containing up to four heteroatoms in each ring in which at least one ofrings (a) and (b) is aromatic; X¹ is C or N when part of an aromaticring or CR¹⁴ when part of a non aromatic ring; X² is N, NR¹³, O,S(O)_(x), CO or CR¹⁴ when part of an aromatic or non-aromatic ring ormay in addition be CR¹⁴R¹⁵ when part of a non aromatic ring; X³ and X⁵are independently N or C; Y¹ is a 0 to 4 atom linker group each atom ofwhich is independently selected from N, NR¹³, O, S(O)_(x), CO and CR¹⁴when part of an aromatic or non-aromatic ring or may additionally beCR¹⁴R¹⁵ when part of a non aromatic ring, Y² is a 2 to 6 atom linkergroup, each atom of Y² being independently selected from N, NR¹³, O,S(O)_(x), CO and CR¹⁴ when part of an aromatic or non-aromatic ring ormay additionally be CR¹⁴R¹⁵ when part of a non aromatic ring; each ofR¹⁴ and R¹⁵ is independently selected from: H; (C₁₋₄)alkylthio; halo;carboxy(C₁₋₄)alkyl; halo(C₁₋₄)alkoxy, halo(C₁₋₄)alkyl; (C₁₋₄)alkyl;(C₂₋₄)alkenyl; (C₁₋₄)alkoxycarbonyl; formyl; (C₁₋₄)alkylcarbonyl;(C₂₋₄)alkenyloxycarbonyl; (C₂₋₄)alkenylcarbonyl; (C₁₋₄)alkylcarbonyloxy;(C₁₋₄)alkoxycarbonyl(C₁₋₄)alkyl; hydroxy; hydroxy(C₁₋₄)alkyl;mercapto(C₁₋₄)alkyl; (C₁₋₄)alkoxy; nitro; cyano; carboxy; amino oraminocarbonyl optionally substituted as for corresponding substituentsin R³; (C₁₋₄)alkylsulphonyl; (C₂₋₄)alkenylsulphonyl; or aminosulphonylwherein the amino group is optionally substituted by (C₁₋₄)alkyl or(C₂₋₄)alkenyl; aryl; aryl(C₁₋₄)alkyl; aryl(C₁₋₄)alkoxy; each R¹³ isindependently H; trifluoromethyl; (C₁₋₄)alkyl optionally substituted byhydroxy, carboxy, (C₁₋₆)alkoxycarbonyl, (C₁₋₆)alkoxy, (C₁₋₆)alkylthio,halo or trifluoromethyl; (C₂₋₄)alkenyl; aryl; aryl (C₁₋₄)alkyl;arylcarbonyl; heteroarylcarbonyl; (C₁₋₄)alkoxycarbonyl;(C₁₋₄)alkylcarbonyl; formyl; (C₁₋₆)alkylsulphonyl; or aminocarbonylwherein the amino group is optionally substituted by(C₁₋₄)alkoxycarbonyl, (C₁₋₄)alkylcarbonyl, (C₂₋₄)alkenyloxycarbonyl,(C₂₋₄)alkenylcarbonyl, (C₁₋₄)alkyl or (C₂₋₄)alkenyl and optionallyfurther substituted by (C₁₋₄)alkyl or (C₂₋₄)alkenyl; each x isindependently 0, 1 or 2; U is CO, SO₂ or CH₂; or R⁴ is a group—X^(1a)—X^(2a)—X^(3a)—X^(4a) in which: X^(1a) is CH₂, CO or SO₂; X^(2a)is CR^(14a)R^(15a); X^(3a) is NR^(13a), O, S, SO₂ or CR^(14a)R^(15a);wherein: each of R^(14a) and R^(15a) is independently selected from thegroups listed above for R¹⁴ and R¹⁵, provided that R^(14a) and R^(15a)on the same carbon atom are not both selected from optionallysubstituted hydroxy and optionally substituted amino; or R^(14a) andR^(15a) together represent oxo; R^(13a) is hydrogen; trifluoromethyl;(C₁₋₆)alkyl; (C₂₋₆)alkenyl; (C₁₋₆)alkoxycarbonyl; (C₁₋₆)alkylcarbonyl;or aminocarbonyl wherein the amino group is optionally substituted by(C₁₋₆)alkoxycarbonyl, (C₁₋₆)alkylcarbonyl, (C₂₋₆)alkenyloxycarbonyl,(C₂₋₆)alkenylcarbonyl, (C₁₋₆)alkyl or (C₂₋₆)alkenyl and optionallyfurther substituted by (C₁₋₆)alkyl or (C₂₋₆)alkenyl; or two R^(14a)groups or an R^(13a) and an R^(14a) group on adjacent atoms togetherrepresent a bond and the remaining R^(13a), R^(14a) and R^(15a) groupsare as above defined; or two R^(14a) groups and two R^(15a) groups onadjacent atoms together represent bonds such that X^(2a) and X^(3a) istriple bonded; X^(4a) is phenyl or C or N linked monocyclic aromatic 5-or 6-membered heterocycle containing up to four heteroatoms selectedfrom O, S and N and: optionally C-substituted by up to three groupsselected from (C₁₋₄)alkylthio; halo; carboxy(C₁₋₄)alkyl;halo(C₁₋₄)alkoxy; halo(C₁₋₄)alkyl; (C₁₋₄)alkyl; (C₂₋₄)alkenyl;(C₁₋₄)alkoxycarbonyl; formyl; (C₁₋₄)alkylcarbonyl;(C₂₋₄)alkenyloxycarbonyl; (C₂₋₄)alkenylcarbonyl; (C₁₋₄)alkylcarbonyloxy;(C₁₋₄)alkoxycarbonyl(C₁₋₄)alkyl; hydroxy; hydroxy(C₁₋₄)alkyl;mercapto(C₁₋₄)alkyl; (C₁₋₄)alkoxy, nitro; cyano; carboxy; amino oraminocarbonyl optionally substituted as for corresponding substituentsin R³; (C₁₋₄)alkylsulphonyl; (C₂₋₄)alkenylsulphonyl; or aminosulphonylwherein the amino group is optionally substituted by (C₁₋₄)alkyl or(C₂₋₄)alkenyl; aryl, aryl(C₁₋₄)alkyl or aryl(C₁₋₄)alkoxy; and optionallyN substituted by trifluoromethyl; (C₁₋₄)alkyl optionally substituted byhydroxy, (C₁₋₆)alkoxy, (C₁₋₆)alkylthio, halo or trifluoromethyl;(C₂₋₄)alkenyl; aryl; aryl(C₁₋₄)alkyl; (C₁₋₄)alkoxycarbonyl;(C₁₋₄)alkylcarbonyl; formyl; (C₁₋₆)alkylsulphonyl; or aminocarbonylwherein the amino group is optionally substituted by(C₁₋₄)alkoxycarbonyl, (C₁₋₄)alkylcarbonyl, (C₂₋₄)alkenyloxycarbonyl,(C₂₋₄)alkenylcarbonyl, (C₁₋₄)alkyl or (C₂₋₄)alkenyl and optionallyfurther substituted by (C₁₋₄)alkyl or (C₂₋₄)alkenyl; n is 0 or 1 and ABis NR¹¹CO, CONR¹¹, CO—CR⁸R⁹, CR⁶R⁷⁻CO, O—CR⁸R⁹, CR⁶R⁷⁻O, NR¹¹—CR⁸R⁹,CR⁶R⁷—NR¹¹, NR¹¹SO₂, CR⁶R⁷—SO₂ or CR⁶R⁷—CR⁸R⁹, provided that when R^(v)and R^(w) are a bond and n=0, B is not NR¹¹, O or SO₂, or n is 0 and ABis NH—CO—NH or NH—CO—O and R^(v)/R^(w) are not a bond; or n is 0 and ABis CR⁶R⁷SO₂NR², CR⁶R⁷CONR² or CR⁶R⁷CH₂NR² and R^(v)/R^(w) are not abond; provided that R⁶ and R⁷, and R⁸ and R⁹ are not both optionallysubstituted hydroxy or amino; and wherein: each of R⁶, R⁷, R⁸ and R⁹ isindependently selected from: H; (C₁₋₆)alkoxy; (C₁₋₆)alkylthio; halo;trifluoromethyl; azido; (C₁₋₆)alkyl; (C₂₋₆)alkenyl;(C₁₋₆)alkoxycarbonyl; (C₁₋₆)alkylcarbonyl; (C₂₋₆)alkenyloxycarbonyl;(C₂₋₆)alkenylcarbonyl; hydroxy, amino or aminocarbonyl optionallysubstituted as for corresponding substituents in R³;(C₁₋₆)alkylsulphonyl; (C₂₋₆)alkenylsulphonyl; or (C₁₋₆)aminosulphonylwherein the amino group is optionally substituted by (C₁₋₆)alkyl or(C₂₋₆)alkenyl; or R⁶ and R⁸ together represent a bond and R⁷ and R⁹ areas above defined; and each R¹¹ is independently H; trifluoromethyl;(C₁₋₆)alkyl; (C₂₋₆)alkenyl; (C₁₋₆)alkoxycarbonyl; (C₁₋₆)alkylcarbonyl;or aminocarbonyl wherein the amino group is optionally substituted by(C₁₋₆)alkoxycarbonyl, (C₁₋₆)alkylcarbonyl, (C₂₋₆)alkenyloxycarbonyl,(C₂₋₆)alkenylcarbonyl, (C₁₋₆)alkyl or (C₂₋₆)alkenyl and optionallyfurther substituted by (C₁₋₆)alkyl or (C₂₋₆)alkenyl.
 2. A compoundaccording to claim 1 wherein Z¹ is N, Z³ is CH or CF and Z², Z⁴ and Z⁵are each CH.
 3. A compound according to claim 1 wherein R¹ is methoxy orfluoro and R^(1a) is H or when Z³ is CR^(1a) it may be C—F.
 4. Acompound according to claim 1 wherein R² is hydrogen.
 5. A compoundaccording to claim 1 wherein R³ is hydrogen or hydroxy substituted inthe 1-or 3-position.
 6. A compound according to claim 1 wherein n is 0and either A is CHOH or CH₂ and B is CH₂ or A is NH and B is CO, andAB(CH₂)_(n) and NR²R⁴ are trans.
 7. A compound according to claim 1wherein R⁴ is —U—R⁵ ₂, the group —U— is —CH₂—, and R⁵ ₂ is an aromaticheterocyclic ring (A) having 8-11 ring atoms including 2-4 heteroatomsof which at least one is N or NR¹³ in which Y² contains 2-3 heteroatoms,one of which is S and 1-2 are N, with one N bonded to X³, or theheterocyclic ring (A) has ring (a) aromatic selected from optionallysubstituted benzo and pyrido and ring (b) non-aromatic and Y² has 3-5atoms including heteroatom bonded to X⁵ selected from NR¹³, O or S,where R13 is other than hydrogen, and NHCO bonded via N to X³, or Obonded to X³.
 8. A compound according to claim 1 wherein R⁵ ₂ isselected from: benzo[1,2,5]thiadiazol-5-yl3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl(4H-benzo[1,4]thiazin-3-one-6-yl) 2,3-dihydro-benzo[1,4]dioxin-6-ylbenzo[1,2,3]thiadiazol-5-yl 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl7-fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4] oxazin-6-yl2-oxo-2,3-dihydro-1H-pyrido[2,3-b]thiazin-7-yl2,3-Dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl3-oxo-3,4-dihydro-2H-pyrido[2,3-b]oxazin-6-yl[1,2,3]thiadiazolo[5,4-b]pyridin-6-yl.
 9. A compound according to claim1, selected from:Trans-4-[(8-Hydroxy-quinolin-2-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide;Trans-4-[(Benzo[1,2,5]thiadiazol-5-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide;Trans-4-[(1H-Pyrrolo[2,3-b]pyridin-2-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide;Trans-4-[(3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-ylmethyl)-amino]-cyclohexanecarboxylic acid (6-methoxy-[1,5]naphthyridin-4-yl)-amide;Trans-4-[(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide;Trans-4-[(Benzo[1,2,3]thiadiazol-5-yl-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide;Trans-4-[(3-Methyl-2-oxo-2,3-dihydro-benzooxazol-6-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide;Trans-4-[(3-Oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide;Trans-4-[(7-Fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide;Trans-4-[(2-Oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazin-7-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide;Trans-4-[(3,4-Dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide;Trans-4-[(Thiazolo[5,4-b]-pyridin-6-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide;Trans-4-[(8-Hydroxy-1-oxo-1,2-dihydro-isoquinolin-3-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide;Trans-4-[(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-6-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide;Trans-4-[(2,3-Dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide;Trans-4-[(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-7-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide;Trans-4-[(6-Nitro-benzo[1,3]dioxol-5-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide;Trans-4-[(6-Amino-benzo[1,3]dioxol-5-ylmenthyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide;Trans-4-[(Benzothiazol-5-ylmethyl)-amino]cyclohexanecarboxylicacid(6-methoxy-[1,5]naphthyridine-4-yl)amide; Trans-4-[(4-Oxo-4 Hpyrido[1,2-a]pyrimidin-2-ylmethyl)-amino]-cyclohexanecarboxylic acid(6-methoxy-[1,5]naphthyridin-4-yl)-amide;Trans-4-[(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-cyclohexanecarboxylicacid [6-(3-amino-propoxy)-[1,5]naphthyridin-4-yl]-amide;Trans-4-[(3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide;Trans-4-[([1,2,3]Thiadiazolo[5,4-b]pyridin-6-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide;Trans-4-(3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-sulfonylamino)-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide;Trans-4-[(7-Fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide;Trans-4-[(8-Nitro-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy)-[1,5]naphthyridin-4-yl)-amide;Trans-4-[(8-Amino-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy)-[1,5]naphthyridin-4-yl)-amide;(R/S)-4-[(3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-ylmethyl)-amino]-cyclohex-1-enecarboxylic acid (6-methoxy-[1,5]naphthyridin-4-yl)-amide;(R/S)-4-[(Benzo[1,2,5]thiadiazol-5-ylmethyl)-amino]-cyclohexenecarboxylic acid (6-methoxy-[1,5]naphthyridin-4-yl)-amide;(R/S)-4-[(Benzo[1,2,3]thiadiazol-5-ylmethyl)-amino]-cyclohex-1-enecarboxylic acid (6-methoxy-[1,5]naphthyridin-4-yl)amide;(R/S)-4-[(2-Oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazin-7-ylmethyl)-amino]-cyclohex-1-enecarboxylic acid (6-methoxy-[1,5]naphthyridin-4-yl)-amide;(R/S)-4-[(7-Fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-amino]-cyclohex-1-enecarboxylic acid (6-methoxy-[1,5]naphthyridin-4-yl)-amide;(R/S)-4-[(2-Oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylmethyl)-amino]-cyclohex-1-enecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide;(R/S)-4-[Carboxymethyl-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-ylmethyl)-amino]-cyclohex-1-enecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide;1-Hydroxy-t-4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-ylmethyl)-amino]-r-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide;1-Hydroxy-t-4-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)-amino]-r-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide;1-Hydroxy-t-4-[(2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]thiazin-7-ylmethyl)-amino]-r-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide;1-Hydroxy-t-4-[(2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazin-7-ylmethyl)-amino]-r-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide;1-Hydroxy-t-4-[(7-bromo-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)-amino]-r-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide;1-Hydroxy-t-4-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylmethyl)-amino]-r-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide;1-Hydroxy-t-4-[(7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)-amino]-r-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide;1-Hydroxy-t-4-[(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridine-2-ylmethyl)-amino]-r-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridine-4-yl)-amide;1-Hydroxy-t-4-[(7-fluoro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)-amino]-r-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide;1-Hydroxy-t-4-[(2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazin-7-ylmethyl)-amino]-r-cyclohexanecarboxylicacid (6-methyl-[1,5]naphthyridin-4-yl)-amide;1-Hydroxy-t-4-[(7-methyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)-amino]-r-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide;1-Hydroxy-t-4-[(7-ethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)-amino]-r-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide;1-Hydroxy-t-4-[(6-oxo-6,7-dihydro-5H-pyridazino[3,4-b][1,4]thiazin-3-ylmethyl)-amino]-r-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide;1-Hydroxy-t-4-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)-amino]-r-cyclohexanecarboxylicacid [6-(2-methoxy-ethoxy)-[1,5]naphthyridin-4-yl]-amide;(1S,3S,4S)-3-Hydroxy-4-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide and(1R,3R,4R)-3-Hydroxy-4-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide;(1R,3R,4R)-3-Hydroxy-4-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide;(1S,3S,4S)-3-Hydroxy-4-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1.4]thiazin-6-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide;(1S,3S,4S)-4-[(7-Chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)-amino]-3-hydroxy-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide and(1R,3R,4R)-4-[(7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)-amino]-3-hydroxy-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide;(1S,3S,4S)-3-Hydroxy-4-[(7-fluoro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide and(1R,3R,4R)-3-Hydroxy-4-[(7-fluoro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide;(1S,3S,4S)-3-Hydroxy-4-[(2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazin-7-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide and(1R,3R,4R)-3-Hydroxy-4-[(2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazin-7-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide;(1S,3S,4S)-3-Hydroxy-4-[(2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]thiazin-7-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide and(1R,3R,4R)-3-Hydroxy-4-[(2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]thiazin-7-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide;(1S,3S,4S)-3-Hydroxy-4-[(6-oxo-6,7-dihydro-5H-8-thia-1,2,5-triaza-naphthalen-3-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide and(1R,3R,4R)-3-hydroxy-4-[6-oxo-6,7-dihydro-5H-8-thia-1,2,5-triaza-naphthalen-3-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide;(1R,3R,4R)-3-Hydroxy-4-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide;(1R,3R,4R)-3-Hydroxy-4-[(7-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide;(1R,3R,4R)-3-Hydroxy-4-[(2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]thiazin-7-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide;(1S,3S,4S)-3-Hydroxy-4-[(7-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide;(1S,3S,4S)-3-Hydroxy-4-[(2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]thiazin-7-ylmethyl)-amino]-cyclohexanecarboxylicacid (6-methoxy-[1,5]naphthyridin-4-yl)-amide;1-Hydroxy-t-4-[(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amino]-r-cyclohexanecarboxylicacid (6-methoxy-[1,5]napthyridin-4-yl)-amide;6-({4-hydroxy-4-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-cyclohexylamino}-methyl)-4H-pyrido[3,2-b][1,4]oxazin-3-one;or a pharmaceutically acceptable salt, solvate or N-oxide thereof.
 10. Amethod of treatment of bacterial infections in mammals, which methodcomprises the administration to a mammal in need of such treatment aneffective amount of a compound according to claim
 1. 11. Apharmaceutical composition comprising a compound according to claim 1,and a pharmaceutically acceptable carrier.
 12. A compound of formula(VI):

wherein one of Z¹, Z², or Z³ is N, and one of the remainder of Z₁, Z₂,Z₃, Z₄, and Z₅ is CR^(1a) and the remainder are CH; R^(v) and R^(w) arehydrogen; R^(v) and R³; or R^(v) and R^(w) together are a bond; R¹ andR^(1a) are independently selected from hydrogen; hydroxy; (C₁₋₆) alkoxyoptionally substituted by (C₁₋₆)alkoxy, amino, piperidyl, guanidino oramidino any of which is optionally N-substituted by one or two(C₁₋₆)alkyl, (C₁₋₆)alkoxycarbonyl, formyl, (C₁₋₆)alkoxycarbonyl, or(C₁₋₆)alkylsulphonyl groups, CONH2, hydroxy, (C₁₋₆)alkylthio,heterocyclylthio, heterocyclyloxy, arylthio, aryloxy,(C₁₋₆)alkyloxycarbonylthio, formylthio, (C₁₋₆)alkylcarbonylthio;(C₁₋₆)alkyloxycarbonyloxy; formyloxy, (C₁₋₆)alkylcarbonyloxy or(C₁₋₆)alkylsulphonyloxy; (C₁₋₆)alkoxy-substituted (C₁₋₆)alkyl; halogen;(C₁₋₆)alkyl; (C₁₋₆)alkylthio; trifluromethyl; nitro; azido;(C₁₋₆)alkoxycarbonyl; formyl; (C₁₋₆)alkylcarbonyl;(C₁₋₆)alkyloxycarbonyloxy; formyloxy; (C₁₋₆)alkylcarbonyloxy;(C₁₋₆)alkyloxycarbonylthio; formylthio; (C₁₋₆)alkylcarbonylthio;(C₁₋₆)alkylsulphonyl; (C₁₋₆)alkylsulphoxide; arylsulphonyl;arylsulphoxide or an amino, piperidyl, guanidino or amidino groupoptionally N-substituted by one or two (C₁₋₆)alkyl,(C₁₋₆)alkoxycarbonyl, formyl, (C₁₋₆)alkylcarbonyl or(C₁₋₆)alkylsulphonyl groups, or when Z¹ is CR^(1a), R¹ and R^(1a) maytogether represent (C₁₋₂)alkylenedioxy; or when Z⁵ is CR^(1a), R^(1a)may be cyano, hydroxymethyl or carboxy; R² is hydrogen, or (C₁₋₄)alkylor (C₂₋₄)alkenyl optionally substituted with 1 to 3 groups selectedfrom: amino optionally substituted by one or two (C₁₋₄)alkyl groups;carboxy; (C₁₋₄)alkoxycarbonyl; (C₁₋₄)alkylcarbonyl;(C₂₋₄)alkenyloxycarbonyl; (C₂₋₄)alkenylcarbonyl; aminocarbonyl whereinthe amino group is optionally substituted by hydroxy, (C₁₋₄)alkyl,hydroxy(C₁₋₄)alkyl, aminocarbonyl(C₁₋₄)alkyl, (C₂₋₄)alkenyl,(C₁₋₄)alkylsulphonyl, trifluoromethylsulphonyl, (C₂₋₄)alkenylsulphonyl,(C₁₋₄)alkoxycarbonyl, (C₁₋₄)alkylcarbonyl, (C₂₋₄)alkenyloxycarbonyl or(C₂₋₄)alkenylcarbonyl; cyano; tetrazolyl; 2-oxo-oxazolidinyl optionallysubstituted by R¹⁰; 3-hydroxy-3-cyclobutene-1,2-dione-4-yl;2,4-thiazolidinedione-5-yl; tetrazol-5-ylaminocarbonyl;1,2,4-triazol-5-yl optionally substituted by R¹⁰;5-oxo-1,2,4-oxadiazol-3-yl; halogen; (C₁₋₄)alkylthio; trifluoromethyl;hydroxy optionally substituted by (C₁₋₄)alkyl, (C₂₋₄)alkenyl,(C₁₋₄)alkoxycarbonyl, (C₁₋₄)alkylcarbonyl, (C₂₋₄)alkenyloxycarbonyl,(C₂₋₄)alkenylcarbonyl; oxo; (C₁₋₄)alkylsulphonyl;(C₂₋₄)alkenylsulphonyl; or (C₁₋₄)aminosulphonyl wherein the amino groupis optionally substituted by (C₁₋₄)alkyl or (C₂₋₄)alkenyl; when R^(v)and R^(w) are a bond, R³ is in the 2- or 3-position and when R^(v) andR^(w) are not a bond, R³ is in the 1-, 2-, or 3-position and R³ is:hydrogen; carboxy; (C₁₋₆)alkoxycarbonyl; aminocarbonyl wherein the aminogroup is optionally substituted by hydroxy, (C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, aminocarbonyl(C₁₋₆)alkyl, (C₂₋₆)alkenyl,(C₁₋₆)alkylsulphonyl, trifluoromethylsulphonyl, (C₂₋₆)alkenylsulphonyl,(C₁₋₆)alkoxycarbonyl, (C₁₋₆)alkylcarbonyl, (C₂₋₆)alkenyloxycarbonyl or(C₂₋₆)alkenylcarbonyl and optionally further substituted by (C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, aminocarbonyl(C₁₋₆)alkyl or (C₂₋₆)alkenyl; cyano;tetrazolyl; 2-oxo-oxazolidinyl optionally substituted by R¹⁰;3-hydroxy-3-cyclobutene-1,2-dione-4-yl; 2,4-thiazolidinedione-5-yl;tetrazol-5-ylaminocarbonyl; 1,2,4-triazol-5-yl optionally substituted byR¹⁰; or 5-oxo-1,2,4-oxadiazol-3-yl; or (C₁₋₄)alkyl or ethenyl optionallysubstituted with any of the groups listed above for R³ and/or 0 to 2groups R¹² independently selected from: halogen; (C₁₋₆)alkylthio;trifluoromethyl; (C₁₋₆)alkoxycarbonyl; (C₁₋₆)alkylcarbonyl;(C₂₋₆)alkenyloxycarbonyl; (C₂₋₆)alkenylcarbonyl; hydroxy optionallysubstituted by (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₁₋₆)alkoxycarbonyl,(C₁₋₆)alkylcarbonyl, (C₂₋₆)alkenyloxycarbonyl, (C₂₋₆)alkenylcarbonyl oraminocarbonyl wherein the amino group is optionally substituted by(C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₁₋₆)alkylcarbonyl or(C₂₋₆)alkenylcarbonyl; amino optionally mono- or disubstituted by(C₁₋₆)alkoxycarbonyl, (C₁₋₆)alkylcarbonyl, (C₂₋₆)alkenyloxycarbonyl,(C₂₋₆)alkenylcarbonyl, (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₁₋₆)alkylsulphonyl,(C₂₋₆)alkenylsulphonyl or aminocarbonyl wherein the amino group isoptionally substituted by (C₁₋₆)alkyl or (C₂₋₆)alkenyl; aminocarbonylwherein the amino group is optionally substituted by (C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, aminocarbonyl(C₁₋₆)alkyl, (C₂₋₆)alkenyl,(C₁₋₆)alkoxycarbonyl, (C₁₋₆)alkylcarbonyl, (C₂₋₆)alkenyloxycarbonyl or(C₂₋₆)alkenylcarbonyl and optionally further substituted by (C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, aminocarbonyl(C₁₋₆)alkyl or (C₂₋₆)alkenyl; oxo;(C₁₋₆)alkylsulphonyl; (C₂₋₆)alkenylsulphonyl; or (C₁₋₆)aminosulphonylwherein the amino group is optionally substituted by (C₁₋₆)alkyl or(C₂₋₆)alkenyl; or hydroxy optionally substituted by (C₁₋₆)alkyl,(C₂₋₆)alkenyl, (C₁₋₆)alkoxycarbonyl, (C₁₋₆)alkylcarbonyl,(C₂₋₆)alkenyloxycarbonyl, (C₂₋₆)alkenylcarbonyl or aminocarbonyl whereinthe amino group is optionally substituted by (C₁₋₆)alkyl, (C₂₋₆)alkenyl,(C₁₋₆)alkylcarbonyl or (C₂₋₆)alkenylcarbonyl; or amino optionally mono-or disubstituted by (C₁₋₆)alkoxycarbonyl, (C₁₋₆)alkylcarbonyl,(C₂₋₆)alkenyloxycarbonyl, (C₂₋₆)alkenylcarbonyl, (C₁₋₆)alkyl,(C₂₋₆)alkenyl, (C₁₋₆)alkylsulphonyl, (C₂₋₆)alkenylsulphonyl oraminocarbonyl wherein the amino group is optionally substituted by(C₁₋₆)alkyl or (C₂₋₆)alkenyl; in addition when R³ is disubstituted witha hydroxy or amino containing substituent and a carboxy containingsubstituent these may optionally together form a cyclic ester or amidelinkage, respectively; n is 0 or 1 and AB is NR¹¹CO, CONR¹¹, CO—CR⁸R⁹,CR⁶R⁷⁻CO, O—CR⁸R⁹, CR⁶R⁷⁻O, NR¹¹—CR⁸R⁹, CR⁶R⁷⁻NR¹¹, NR¹¹SO₂, CR⁶R⁷—SO₂or CR⁶R⁷⁻CR⁸R⁹, provided that when R^(v) and R^(w) are a bond and n=0, Bis not NR¹¹, O or SO₂, or n is 0 and AB is NH—CO—NH or NH—CO—O andR^(v)/R^(w) are not a bond; or n is 0 and AB is CR⁶R⁷SO₂NR², CR⁶R⁷CONR²or CR⁶R⁷CH₂NR² and R^(v)/R^(w) are not a bond; provided that R⁶ and R⁷,and R⁸ and R⁹ are not both optionally substituted hydroxy or amino: andwherein: each of R⁶, R⁷, R⁸ and R⁹ is independently selected from: H;(C₁₋₆)alkoxy; (C₁₋₆)alkylthio; halo; trifluoromethyl; azido;(C₁₋₆)alkyl; (C₂₋₆)alkenyl; (C₁₋₆)alkoxycarbonyl; (C₁₋₆)alkylcarbonyl;(C₂₋₆)alkenyloxycarbonyl; (C₂₋₆)alkenylcarbonyl; hydroxy, amino oraminocarbonyl optionally substituted as for corresponding substituentsin R³; (C₁₋₆)alkylsulphonyl; (C₂₋₆)alkenylsulphonyl; or(C₁₋₆)aminosulphonyl wherein the amino group is optionally substitutedby (C₁₋₆)alkyl or (C₂₋₆)alkenyl; or R⁶ and R⁸ together represent a bondand R⁷ and R⁹ are as above defined; R¹⁰ is selected from (C₁₋₄)alkyl and(C₂₋₄) alkenyl either of which may be optionally substituted by a groupR¹² as defined above; carboxy; aminocarbonyl wherein the amino group isoptionally substituted by hydroxy, (C₁₋₆)alkyl, (C₂₋₆)alkenyl,(C₁₋₆)alkylsulphonyl, trifluoromethylsulphonyl, (C₂₋₆)alkenylsulphonyl,(C₁₋₆)alkoxycarbonyl, (C₁₋₆)alkylcarbonyl, (C₂₋₆)alkenyloxycarbonyl or(C₂₋₆)alkenylcarbonyl and optionally further substituted by (C₁₋₆)alkylor (C₂₋₆)alkenyl; (C₁₋₆)alkylsulphonyl; trifluoromethylsulphonyl;(C₂₋₆)alkenylsulphonyl; (C₁₋₆)alkoxycarbonyl; (C₁₋₆)alkylcarbonyl;(C₂₋₆)alkenyloxycarbonyl; and (C₂₋₆)alkenylcarbonyl; and each R¹¹ isindependently H; trifluoromethyl; (C₁₋₆)alkyl; (C₁₋₆)alkoxycarbonyl;(C₁₋₆)alkylcarbonyl; or aminocarbonyl wherein the amino group isoptionally substituted by (C₁₋₆)alkoxycarbonyl, (C₁₋₆)alkylcarbonyl,(C₂₋₆)alkenyloxycarbonyl, (C₂₋₆)alkenyloxycarbonyl, (C₁₋₆)alkyl or(C₂₋₆)alkenyl and optionally further substituted by (C₁₋₆)alkyl or(C₂₋₆)alkenyl.
 13. A compound of formula (VII):

wherein one of Z¹, Z², or Z³ is N, one of the remainder of Z¹, Z², Z³,Z⁴, and Z⁵ is CR^(1a) and the remainder are CH; R^(v) and R^(w) arehydrogen; R^(v) is R³; or R^(v) and R^(w) together are a bond; R¹ andR^(1a) are independently selected from hydrogen; hydroxy; (C₁₋₆) alkoxyoptionally substituted by (C₁₋₆)alkoxy, amino, piperidyl, guanidino oramidino any of which is optionally N-substituted by one or two(C₁₋₆)alkyl, (C₁₋₆)alkoxycarbonyl, formyl, (C₁₋₆)alkylcarbonyl, or(C₁₋₆)alkylsulphonyl groups, CONH2, hydroxy, (C₁₋₆)alkylthio,heterocyclylthio, heterocyclyloxy, arylthio, aryloxy,(C₁₋₆)alkyloxycarbonylthio; formylthio; (C₁₋₆)alkylcarbonylthio;(C₁₋₆)alkyloxycarbonyloxy; formyloxy, (C₁₋₆)alkylcarbonyloxy or(C₁₋₆)alkylsulphonyloxy; (C₁₋₆)alkoxy-substituted (C₁₋₆)alkyl; halogen;(C₁₋₆)alkyl; (C₁₋₆)alkylthio; trifluromethyl; nitro; azido;(C₁₋₆)alkoxycarbonyl; formyl; (C₁₋₆)alkylcarbonyl;(C₁₋₆)alkyloxycarbonyloxy; formyloxy; (C₁₋₆)alkylcarbonyloxy;(C₁₋₆)alkyloxycarbonylthio; formylthio; (C₁₋₆)alkylcarbonylthio;(C₁₋₆)alkylsulphonyl; (C₁₋₆)alkylsulphoxide; arylsulphonyl;arylsulphoxide or an amino, piperidyl, guanidino or amidino groupoptionally N-substituted by one or two (C₁₋₆)alkyl,(C₁₋₆)alkoxycarbonyl, formyl, (C₁₋₆)alkylcarbonyl or(C₁₋₆)alkylsulphonyl groups, or when Z¹ is CR^(1a), R^(1a) may togetherrepresent (C₁₋₂)alkylenedioxy; or when Z⁵ is CR^(1a), R^(1a) may insteadby cyano, hydroxymethyl or carboxy; R² is hydrogen, or (C₁₋₄)alkyl or(C₂₋₄)alkenyl optionally substituted with 1 to 3 groups selected from:amino optionally substituted by one or two (C₁₋₄)alkyl groups; carboxy;(C₁₋₄)alkoxycarbonyl; (C₁₋₄)alkylcarbonyl; (C₂₋₄)alkenyloxycarbonyl;(C₂₋₄)alkenylcarbonyl; aminocarbonyl wherein the amino group isoptionally substituted by hydroxy, (C₁₋₄)alkyl, hydroxy(C₁₋₄)alkyl,aminocarbonyl(C₁₋₄)alkyl, (C₂₋₄)alkenyl, (C₁₋₄)alkylsulphonyl,trifluoromethylsulphonyl, (C₂₋₄)alkenylsulphonyl, (C₁₋₄)alkoxycarbonyl,(C₁₋₄)alkylcarbonyl, (C₂₋₄)alkenyloxycarbonyl or (C₂₋₄)alkenylcarbonyl;cyano; tetrazolyl; 2-oxo-oxazolidinyl optionally substituted by R¹⁰;3-hydroxy-3-cyclobutene-1,2-dione-4-yl; 2,4-thiazolidinedione-5-yl;tetrazol-5-ylaminocarbonyl; 1,2,4-triazol-5-yl optionally substituted byR¹⁰; 5-oxo-^(1,2,4)-oxadiazol-3-yl; halogen; (C₁₋₄)alkylthio;trifluoromethyl; hydroxy optionally substituted by (C₁₋₄)alkyl,(C₂₋₄)alkenyl, (C₁₋₄)alkoxycarbonyl; (C₁₋₄)alkylcarbonyl;(C₂₋₄)alkenyloxycarbonyl, (C₂₋₄)alkenylcarbonyl; oxo;(C₁₋₄)alkylsulphonyl; (C₂₋₄)alkenylsulphonyl; or (C₁₋₄)aminosulphonylwherein the amino group is optionally substituted by (C₁₋₄)alkyl or(C₂₋₄)alkenyl; when R¹⁰ and R^(w) are a bond, R³ is in the 2- or3-position and when R^(v) and R^(w) are not a bond, R³ is in the 1-, 2-,3-, and 4-position and R³ is; hydrogen; carboxy; (C₁₋₆)alkoxycarbonyl;aminocarbonyl wherein the amino group is optionally substituted byhydroxy, (C₁₋₆)alkyl, hydroxy(C₁₋₄)alkyl, aminocarbonyl(C₁₋₆)alkyl,(C₂₋₆)alkenyl, (C₁₋₆)alkylsulphonyl, trifluoromethylsulphonyl,(C₂₋₆)alkenylsulphonyl, (C₁₋₆)alkoxycarbonyl, (C₁₋₆)alkylcarbonyl,(C₂₋₆)alkenyloxycarbonyl or (C₂₋₆)alkenylcarbonyl and optionally furthersubstituted by (C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl, aminocarbonyl(C₁₋₆)alkylor (C₂₋₆)alkenyl; cyano; tetrazolyl; 2-oxo-oxazolidinyl optionallysubstituted by R¹⁰; 3-hydroxy-3-cyclobutene-1,2-dione-4-yl;2,4-thiazolidinedione-5-yl; tetrazol-5-ylaminocarbonyl;1,2,4-triazol-5-yl optionally substituted by R¹⁰; or5-oxo-1,2,4-oxadiazol-3-yl; or (C₁₋₄)alkyl or ethenyl optionallysubstituted with any of the groups listed above for R³ and/or 0 to 2groups R¹² independently selected from: halogen; (C₁₋₆)alkylthio;trifluoromethyl; (C₁₋₆)alkoxycarbonyl; (C₁₋₆)alkylcarbonyl;(C₂₋₆)alkenyloxycarbonyl; (C₂₋₆)alkenylcarbonyl; hydroxy optionallysubstituted by (C_(1-6 )alkyl, (C) ₂₋₆)alkenyl, (C₁₋₆)alkoxycarbonyl,(C₁₋₆)alkylcarbonyl, (C₂₋₆)alkenyloxycarbonyl, (C₂₋₆)alkenylcarbonyl oraminocarbonyl wherein the amino group is optionally substituted by(C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₁₋₆)alkylcarbonyl or(C₂₋₆)alkenylcarbonyl; amino optionally mono- or disubstituted by(C₁₋₆)alkoxycarbonyl, (C₁₋₆)alkylcarbonyl, (C₂₋₆)alkenyloxycarbonyl,(C₂₋₆)alkenylcarbonyl, (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₁₋₆)alkylsulphonyl,(C₂₋₆)alkenylsulphonyl or aminocarbonyl wherein the amino group isoptionally substituted by (C₁₋₆)alkyl or (C₂₋₆)alkenyl; aminocarbonylwherein the amino group is optionally substituted by (C₁₋₆)alkyl,hydroxy (C₁₋₆)alkyl, aminocarbonyl(C₁₋₆)alkyl, (C₂₋₆)alkenyl,(C₁₋₆)alkoxycarbonyl, (C₁₋₆)alkylcarbonyl, (C₂₋₆)alkenyloxycarbonyl or(C₂₋₆)alkenylcarbonyl and optionally further substituted by (C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, aminocarbonyl(C₁₋₆)alkyl or (C₂₋₆)alkenyl; oxo;(C₁₋₆)alkylsulphonyl; (C₂₋₆)alkenylsulphonyl; or (C₁₋₆)aminosulphonylwherein the amino group is optionally substituted by (C₁₋₆)alkyl or(C₂₋₆)alkenyl; or hydroxy optionally substituted by (C₁₋₆)alkyl,(C₂₋₆)alkenyl, (C₁₋₆)alkoxycarbonyl, (C₁₋₆)alkylcarbonyl,(C₂₋₆)alkenyloxycarbonyl, (C₂₋₆)alkenylcarbonyl or aminocarbonyl whereinthe amino group is optionally substituted by (C₁₋₆)alkyl, (C₂₋₆)alkenyl,(C₁₋₆)alkylcarbonyl or (C₂₋₆)alkenylcarbonyl; or amino optionally mono-or disubstituted by (C₁₋₆)alkoxycarbonyl, (C₂₋₆)alkylcarbonyl,(C₂₋₆)alkenyloxycarbonyl, (C₂₋₆)alkenylcarbonyl, (C₁₋₆)alkyl,(C₂₋₆)alkenyl, (C₁₋₆)alkylsulphonyl, (C₂₋₆)alkenylsulphonyl oraminocarbonyl wherein the amino group is optionally substituted by(C₁₋₆)alkyl or (C₂₋₆)alkenyl; in addition when R³ is disubstituted witha hydroxy or amino containing substituent and a carboxy containingsubstituent these may optionally together form a cyclic ester or amidelinkage, respectively; provided that when R³ is in the 4-position it isnot optionally substituted hydroxyl or amino; n is 0 or 1 and AB isNR¹¹CO, CONR¹¹, CO—CR⁸R⁹, CR⁶R⁷⁻CO, O—CR⁸R⁹, CR⁶R⁷⁻O, NR¹¹—CR⁸R⁹, CR⁶R⁷⁻NR¹¹, NR¹¹SO₂, CR⁶F⁷—SO₂ or CR⁶R⁷⁻CR⁸R⁹, provided that when R^(v) andR^(w) are a bond and n=0, B is not NR¹¹, O or SO₂, or n is 0 and AB isNH—CO—NH or NH—CO—O and R^(v)/R^(w) are not a bond; or n is 0 and AB isCR⁶R⁷SO₂NR², CR⁶R⁷CONR² or CR⁶R⁷CH₂NR² and R^(v)/R^(w) are not a bond;provided that R⁶ and R⁷, and R⁸ and R⁹ are not both optionallysubstituted hydroxy or amino; and wherein; each of R⁶, R⁷, R⁸ and R⁹ isindependently selected from; H; (C₁₋₆)alkoxy; (C₁₋₆)alkylthio; halo;trifluoromethyl; azido; (C₁₋₆)alkyl; (C₂₋₆)alkenyl;(C₁₋₆)alkoxycarbonyl; (C₁₋₆)alkylcarbonyl; (C₂₋₆)alkenyloxycarbonyl;(C₂₋₆)alkenylcarbonyl; hydroxy, amino or aminocarbonyl optionallysubstituted as for corresponding substituents in R³;(C₁₋₆)alkylsulphonyl; (C₁₋₆)alkenylsulphonyl; or (C₁₋₆)aminosulphonylwherein the amino group is optionally substituted by (C₁₋₆)alkyl or(C₂₋₆)alkenyl; or R⁶ and R⁸ together represent a bond and R⁷ and R⁹ areas above defined; R¹⁰ is selected from (C₁₋₄)alkyl and (C₂₋₄)alkenyleither of which may be optionally substituted by a group R¹² as definedabove; carboxy; aminocarbonyl wherein the amino group is optionallysubstituted by hydroxy, (C₁₋₆)alkyl, (C₂₋₆)alkenyl,(C₁₋₆)alkylsulphonyl, trifluoromethylsulphonyl, (C₁₋₆)alkenylsulphonyl,(C₁₋₆)alkoxycarbonyl, (C₁₋₆)alkylcarbonyl, (C₂₋₆)alkenyloxycarbonyl or(C₂₋₆)alkenylcarbonyl and optionally further substituted by (C₁₋₆)alkylor (C₂₋₆)alkenyl; (C₁₋₆)alkylsulphonyl; trifluoromethylsulphonyl;(C₂₋₆)alkenylsulphonyl; (C₁₋₆)alkoxycarbonyl; (C₁₋₆)alkylcarbonyl;(C₂₋₆)alkenyloxycarbonyl; and (C₂₋₆)alkenylcarbonyl; and each R¹¹ isindependently H; trifluoromethyl; (C₁₋₆)alkyl; (C₂₋₆)alkenyl;(C₁₋₆)alkoxycarbonyl; (C₁₋₆)alkylcarbonyl; or aminocarbonyl wherein theamino group is optionally substituted by (C₁₋₆)alkoxycarbonyl;(C₁₋₆)alkylcarbonyl, (C₂₋₆)alkenyloxycarbonyl, (C₂₋₆)alkenylcarbonyl,(C₁₋₆)alkyl or (C₂₋₆)alkenyl and optionally further substituted by(C₁₋₆)alkyl or (C₂₋₆)alkenyl.
 14. The method of claim 10 wherein themammal is human.